Eccentric Muscle Contractions: Risks and Benefits

fphys-10-00536 May 2, 2019 Time: 17:45 # 1

REVIEW

published: 03 May 2019

doi: 10.3389/fphys.2019.00536

Edited by:

Dario Coletti,

Sapienza University of Rome, Italy

Reviewed by:

Damien Vitiello,

Université Paris Descartes, France

Nissrine Daou,

Pierre and Marie Curie University,

France

*Correspondence:

Stéphanie Hody

[email protected]

Specialty section:

This article was submitted to

Striated Muscle Physiology,

a section of the journal

Frontiers in Physiology

Received: 10 December 2018

Accepted: 15 April 2019

Published: 03 May 2019

Citation:

Hody S, Croisier J-L, Bury T,

Rogister B and Leprince P (2019)

Eccentric Muscle Contractions: Risks

and Beneﬁts. Front. Physiol. 10:536.

doi: 10.3389/fphys.2019.00536

Eccentric Muscle Contractions:

Risks and Beneﬁts

Stéphanie Hody

, Jean-Louis Croisier

, Thierry Bury

, Bernard Rogister

2,3,4

and

Pierre Leprince

2,4

Department of Motricity Sciences, University of Liège, Liege, Belgium,

GIGA-Neurosciences, University of Liège, Liege,

Belgium,

Department of Neurology, The University Hospital Center, University of Liège, Liege, Belgium,

GIGA – Laboratory

of Nervous System Disorders and Therapy, University of Liège, Liege, Belgium

Eccentric contractions, characterized by the lengthening of the muscle-tendon complex,

present several unique features compared with other types of contractions, which may

lead to unique adaptations. Due to its speciﬁc physiological and mechanical properties,

there is an increasing interest in employing eccentric muscle work for rehabilitation and

clinical purposes. However, unaccustomed eccentric exercise is known to cause muscle

damage and delayed pain, commonly deﬁned as “Delayed-Onset Muscular Soreness”

(DOMS). To date, the most useful preventive strategy to avoid these adverse effects

consists of repeating sessions involving submaximal eccentric contractions whose

intensity is progressively increased over the training. Despite an increased number

of investigations focusing on the eccentric contraction, a signiﬁcant gap still remains

in our understanding of the cellular and molecular mechanisms underlying the initial

damage response and subsequent adaptations to eccentric exercise. Yet, unraveling

the molecular basis of exercise-related muscle damage and soreness might help

uncover the mechanistic basis of pathological conditions as myalgia or neuromuscular

diseases. In addition, a better insight into the mechanisms governing eccentric training

adaptations should provide invaluable information for designing therapeutic interventions

and identifying potential therapeutic targets.

Keywords: skeletal muscle, eccentric contraction, exercise-induced muscle damage (EIMD), delayed-onset

muscle soreness (DOMS), eccentric muscle training

INTRODUCTION

An eccentric (lengthening) muscle contraction occurs when a force applied to the muscle exceeds

the momentary force produced by the muscle itself, resulting in the forced lengthening of the

muscle-tendon system while contracting (Lindstedt et al., 2001). During this process, the muscle

absorbs energy developed by an external load, explaining why eccentric action is also called

“negative work” as opposed to concentric (shortening) contraction or “positive work” (Abbott et al.,

1952). Although not always obvious, eccentric muscle contractions are an integral part of most

movements during daily or sport activities. Skeletal muscles contract eccentrically to support the

weight of the body against gravity and to absorb shock or to store elastic recoil energy in preparation

for concentric (or accelerating) contractions (LaStayo et al., 2003b). The slowing-down role of such

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Hody et al. Eccentric Exercise

contractions is classically illustrated by downhill running or

walking down the stairs during which the eccentric work of the

knee extensor muscles is accentuated (Gault and Willems, 2013).

Compared to concentric or isometric (constant length)

contractions, eccentric muscle actions possess several unique

features that may be responsible for unique adaptations (Guilhem

et al., 2010; Duchateau and Baudry, 2014). Greater forces

are generated during eccentric contraction compared to other

contraction types for a given angular velocity (Hortobagyi and

Katch, 1990). In addition, eccentric contractions require less

motor unit activation and consume less oxygen and energy

for a given muscle force than concentric contractions (Abbott

et al., 1952). Indeed, the metabolic cost required for eccentric

exercise is approximately fourfold lower than for the same

exercise performed concentrically. Reduced cardiorespiratory

and hemodynamic responses have been reported following

eccentric exercise when compared to concentric exercise at

the same absolute workload (Overend et al., 2000; Meyer

et al., 2003). While many questions remains unanswered,

it is well accepted that neural strategies controlling eccentric

contractions considerably diﬀer from concentric or isometric

contractions (Duchateau and Baudry, 2014). Diﬀerences are

detected on the level of the contracting muscle as well as

on the cortical level. Most studies indicate a reduced central

activation (evidenced by a lower EMG amplitude) during

maximal eccentric contractions than maximal concentric or

isometric contractions. This has implications on eccentric

coordination: ﬁne motor control in eccentrically biased actions

appears more diﬃcult as fewer motor-units are required for the

same work (Hoppeler, 2016). The twitch interpolation technique

also revealed a greater voluntary deﬁcit in eccentric compared

to concentric contractions, such that untrained individuals are

usually unable to fully activate their muscles during maximal

eccentric muscle contractions. Further characteristics of eccentric

contraction are a greater cortical excitability but a lower motor

units discharge. Collectively, the mechanisms underpinning the

unique features of eccentric contraction are not well understood

(Hoppeler and Herzog, 2014).

Due to its speciﬁc physiological and mechanical properties,

the eccentric contraction has gained a growing interest in several

ﬁelds. Besides its interest in sport training or in physical medicine

and rehabilitation (Croisier et al., 2002; Kjaer and Heinemeier,

2014; Vogt and Hoppeler, 2014), evidence is accumulating

regarding the beneﬁts of eccentric exercise in special populations

of aged individuals or patients with chronic health diseases

such as neuromuscular pathologies (Roig et al., 2008; Gault and

Willems, 2013; Isner-Horobeti et al., 2013; Hyldahl and Hubal,

2014). Indeed, the two main deﬁning properties of eccentric

contraction “highest forces and lower energy requirement” makes

this contraction regime a judicious alternative to conventional

muscle training. To date, it is well accepted that the beneﬁts

of eccentric exercise transcend improved muscle function,

as this mode of training has been shown to induce a number

of favorable repercussions on neural drive or health-related

factors (Paschalis et al., 2010, 2013). For many years, eccentric

regime has been largely used in sport training to improve

maximal muscular strength, power as well as coordination during

eccentric tasks. Robust evidence support its wide prescription

in the sport rehabilitation ﬁeld, notably in the treatment

of tendinopathies (Croisier et al., 2007; Kaux et al., 2013).

In addition, implementing eccentric exercise in athletes showed

its eﬀectiveness to prevent sport injuries such as hamstring strain

(Croisier et al., 2002). While research has mainly focused on

the functional outcomes following eccentric resistance training

using high-loads, the potential of low/moderate load regimes

received much attention over the last decade (LaStayo et al.,

2014; Hoppeler, 2016). With the increasing consideration of

the physical activity in numerous medical ﬁelds over the last

decades, a novel training modality based on low to moderate load

ECC exercise has emerged. This modality, referred as RENEW

(Resistance Exercise via Eccentric Work) by LaStayo et al. (2014),

appears to result in similar gains in muscle strength and volume

as traditional strength training. Since eccentric modality provides

a strong mechanical stress at a lower metabolic cost (Lastayo et al.,

1999), it appears particularly suitable for training individuals with

medical conditions associated to muscle wasting and reduction

in muscle strength, mobility and aerobic capacity (Hoppeler,

2016). Eccentric training is increasingly proposed to patients

with cardiorespiratory problems, sarcopenia of old age, cachexia,

diabetes type 2, neurological and musculoskeletal diseases (Julian

et al., 2018). Along with the positive eﬀects on the muscle

function, aerobic eccentric exercise induces speciﬁc eﬀects on

muscle energetic metabolism, insulin resistance and blood lipid

proﬁle, reducing disease risks. It is thus recognized as a promising

lifestyle factor to combat obesity and dyslipidemias (Paschalis

et al., 2010; Julian et al., 2018, 2019).

However, despite the above-mentioned advantages, the use

of eccentric exercise in clinical conditions has been frequently

the object of contrasting opinions, because of its potential

undesirable associated eﬀects. Indeed, eccentric exercise induces

greater muscle damage and negative functional consequences in

an healthy naïve muscle than other types of exercise (Friden and

Lieber, 1992). Indeed, the combination of high force and reduced

recruitment of ﬁber number during eccentric contractions

causes a high mechanical stress on the involved structures that

may lead to focal microlesions of the muscle ﬁbers (Lieber

and Friden, 1999). Numerous histological studies described

widespread Z-line streaming with myoﬁbrillar disruption and

necrosis following intense and/or unaccustomed eccentric

exercise (Friden and Lieber, 1998; Crameri et al., 2007; Lauritzen

et al., 2009). The sarcomeric disorganization has been associated

with disruptions to the sarcolemma and the extracellular

matrix, swelling of mitochondria, dilation of the transverse

tubule system and fragmentation of the sarcoplasmic reticulum

(Takekura et al., 2001; Crameri et al., 2004). Sarcolemmal

disruption may be highlighted by the appearance of sarcoplasmic

proteins into the blood (as creatine kinase, CK and myoglobin,

Mb) or by the cytoplasmic accumulation of proteins that

are normally not present in muscle ﬁbers (as albumin and

immunoglobulins) (McNeil and Khakee, 1992; Clarkson and

Hubal, 2002). Vital dye such as Evans blue is also used in

rodents to demonstrate increased sarcolemmal permeability

(Hamer et al., 2002). Damage to extracellular matrix and

connective tissue components also occur following a novel

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Hody et al. Eccentric Exercise

eccentric exercise (Brown et al., 1997; Crameri et al., 2007).

Morphological abnormalities observed immediately after exercise

gradually extent to a larger number of muscle ﬁbers and appear

exacerbated 2–3 days post-exercise (Friden et al., 1983a). These

observations have led authors to deﬁne primary and secondary

damage phases (Morgan and Allen, 1999). Both human and

animal studies supported that Type II (in particular IIb) muscle

ﬁbers are more damaged after eccentric exercise than Type I ﬁbers

(Friden et al., 1983b; Jones et al., 1986; Lieber and Friden, 1988).

Several hypotheses could explain the higher susceptibility of Type

II ﬁbers to exercise-induced muscle damage (EIMD). Among

these are diﬀerences in their structural composition (Z-line, ﬁber

type speciﬁc protein isoforms such as titin), a reduced oxidative

capacity, a lower ability to regulate calcium homeostasis or a

selective recruitment of fast-twitch muscle ﬁbers during eccentric

contraction (Lieber and Friden, 1999; McHugh et al., 1999a;

Byrne et al., 2004).

The EIMD manifests itself by a range of clinical symptoms

including delayed-onset muscle soreness (DOMS), stiﬀness,

swelling and various functional deﬁcits such as a loss in

force generating capacity or decreased proprioceptive function

(Clarkson, 1992). To avoid the invasive nature of muscle

biopsies, these clinical manifestations as well as the plasma CK

activity are frequently used to indirectly assess the presence

of muscle damage (Warren et al., 1999; Clarkson and Hubal,

2002). The magnitude of changes in EIMD indirect markers

(in particular, the plasma CK activity) shows a marked inter-

individual variability even when subjects are submitted to

standardized eccentric protocols (Clarkson et al., 1992; Nosaka

and Clarkson, 1996; Hody et al., 2013c). Multiple factors as

muscle architecture, muscle typology, individual ﬁtness, age, sex,

and genetic variability may contribute to the wide inter-subject

variability in the response to eccentric exercise (Vincent and

Vincent, 1997; Clarkson and Hubal, 2002; Yamin et al., 2007;

Hody et al., 2009; Hyldahl and Hubal, 2014). Even if DOMS

and associated clinical symptoms spontaneously disappear after

few days, these negative consequences can delay or disturb

rehabilitation and/or training programs. Exercise is necessary to

maintain a good health and to prevent physical inactivity-related

diseases, but unpleasant sensations resulting from unaccustomed

exercise can discourage people to continue physical activity.

Moreover, due to the mechanical fragility, the risk of further

injuries (e.g., muscle tears or ligament rupture) increases if

intense physical activities are performed during a DOMS episode

or the following days (Nicol et al., 2006). It is worth noting that

muscle soreness disappears before the full recovery of muscle

function, further elevating the injury incidence (Strojnik et al.,

2001). Although exceptional, extreme CK and Mb elevations

associated with EIMD could be severe enough to provoke a

kidney tubulopathy (Sayers et al., 1999).

Given the risks and drawbacks related to the occurrence

of EIMD described above, the development of strategies to

prevent or reduce the intensity of its clinical manifestations

has become a primary goal of many studies. The most

commonly used approaches include stretching, cryotherapy,

electric or manual therapies, whole-body vibration or nutritional

and pharmacological interventions (Cheung et al., 2003;

Barnett, 2006; Bloomer, 2007; Howatson and van Someren,

2008). Despite the large number of clinical trials, there are

very few evidence-based guidelines for the application of these

interventions. The inconsistencies in the dose and frequency

of the investigated interventions may account for the lack

of consensus regarding their eﬃcacy. Conversely, there is

unequivocal evidence that a ﬁrst bout of eccentric exercise confers

protection against EIMD following a subsequent bout of the

similar exercise. This muscle adaptation process, commonly

called “the repeated-bout eﬀect” (RBE), is characterized by

reduced increases in muscular proteins in the blood, attenuated

DOMS, less muscle swelling, reduced abnormality in echo

intensity of B-mode ultrasound and/or magnetic resonance

images and faster recovery of muscle strength and range of

motion following the repeated bout (McHugh, 2003; Nosaka

and Aoki, 2011). Although a signiﬁcant protective eﬀect occurs

after a single eccentric bout (Clarkson et al., 1992; Nosaka and

Clarkson, 1995), the adaptive process appears more complete

after several sessions (Croisier et al., 1999; Hody et al., 2011).

The RBE seems to imply long-lasting adaptation since it

persists for several weeks and even up to 6 months but

the magnitude of the protection decreases over time (Nosaka

et al., 2001, 2005). It is interesting to note that the magnitude

of the protective eﬀect is not necessarily dependent on the

severity of the initial muscle damage. It has been demonstrated

that repeating bouts of “non-damaging” eccentric exercise can

provide strong protective adaptations against subsequent bouts

of maximal eccentric exercise (Chen et al., 2013). Therefore, to

date, performing repeated sessions with submaximal eccentric

contractions appears to be the most eﬃcient strategy to induce

eccentric training-induced adaptations that would prevent

further EIMD and DOMS. The demonstration that eccentric

actions can be performed without damage and soreness allowed

considering the potential of eccentric trainings in medical

conditions. Studies conducted ﬁrst with healthy subjects and

then, with patient populations, have supported the application

of eccentric trainings as a safe, feasible and eﬃcient strategy for

rehabilitation purposes (LaStayo et al., 2000; Hoppeler, 2016).

Numerous studies have attempted to elucidate the mechanisms

underlying the RBE, but this feature of the skeletal muscle is

not fully understood (McHugh et al., 1999a; McHugh, 2003;

Nosaka and Aoki, 2011).

Despite considerable amount of available data at the clinical

and histological levels, a signiﬁcant gap still remains in the

understanding of the mechanisms that mediate morphological,

cellular, and molecular responses to muscle damaging eccentric

exercise (Hoppeler and Herzog, 2014). In addition, the

molecular events underlying the speciﬁc eccentric training

muscle adaptations are not fully understood (McHugh, 2003;

Nosaka and Aoki, 2011). This review begins by describing the

potential mechanisms leading to muscle damage and soreness

following unaccustomed eccentric exercise. Then, are discussed

the current knowledge of the eccentric training-induced

adaptations including the main hypotheses of the protective eﬀect

against EIMD. Finally, the multiple applications of eccentric

training, justifying the need of an improved understanding of its

underlying molecular and cellular mechanisms, are exposed.

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UNACCUSTOMED ECCENTRIC

EXERCISE

Mechanisms of Exercise-Induced

Muscle Damage

It is generally accepted that the damage process is initiated

due to a lack of homogeneity in sarcomeres stretching

(asymmetric lengthening). This theory initially proposed by

Morgan (1990) suggests that during eccentric contractions, the

weakest sarcomeres or even half-sarcomeres will absorb most

of the length change (Morgan, 1990). These may be stretched

beyond the point of myoﬁlament overlap resulting in disrupted

or “popped” sarcomeres. In line with this proposal, several

studies have clearly shown that the length of the muscle during

eccentric contraction is a critical factor in determining the extent

of damage (Talbot and Morgan, 1998). Eccentric contractions

performed at longer muscle length results in greater symptoms

of damage than similar contractions at shorter muscle length

(Lieber and Friden, 1993).

The initial mechanical damage would trigger a cascade of

events leading to more severe secondary damage (Figure 1).

Loss of calcium homeostasis, possible inﬂammatory reaction

and reactive oxygen species (ROS) production are thought to

contribute to the secondary damage phase. The disturbances in

homeostasis observed following unaccustomed eccentric

exercise may be the consequence of membrane damage

(Friden and Lieber, 2001) or opening of stretch-activated

channels (Overgaard et al., 2002). Abnormal increase in

calcium concentration inside muscle cells is responsible for

the activation of muscle proteases, named calpains. Since these

proteases cleave important structural proteins in charge of

myoﬁbril integrity (as desmin and alpha-actinin), they have been

suggested to contribute to EIMD. The degradation of proteins

released from myoﬁbrillar structures by the calpains could

be enhanced by other proteolytic pathways as the ubiquitin–

proteasome system (Raastad et al., 2010). Activation of calpains

may also result in the destruction of membrane constituents,

which in turn, will increase calcium entry. Elevated calcium

concentrations in skeletal muscle mitochondria, which can

alter mitochondrial respiratory function, also occur following

unaccustomed eccentric exercise (Rattray et al., 2011, 2013).

This calcium overload may be associated with the opening

of the mitochondrial permeability transition pore (mPTP)

leading to the activation of cell death signaling or with the

increased calpain proteolytic activity which is capable of targeting

proteins resulting in mitochondrial dysfunction. Furthermore,

the increased calpains activity can promote neutrophils and

macrophages activation, leading to ROS production (Powers and

Jackson, 2008). Besides the clinical symptoms associated with

EIMD (such as DOMS and decline in muscle strength), EIMD

have been reported to induce metabolic consequences at the acute

phase: decreased glucose uptake and insulin sensitivity, impaired

glycogen synthesis, elevated metabolic rate and a shift toward

non-oxidative metabolism (Tee et al., 2007).

Inﬂammatory and Immune Responses

to Eccentric Exercise

While the development of an inﬂammatory reaction after

eccentric exercise has been debated (Yu et al., 2002; Malm and Yu,

2012), many studies have now provided clear evidence of systemic

and local inﬂammatory responses in both rodents and humans

following various types of eccentric exercise (Peake J. et al., 2005;

Paulsen et al., 2012). However, in contrast to extensive works

describing the histological and clinical signs associated to EIMD,

the mechanisms underlying the inﬂammation-immune responses

and the subsequent regenerative events are less well understood

(Peake J. et al., 2005; Paulsen et al., 2012). The inﬂammation

processes following damaging exercise was initially considered as

a detrimental event due to its association with muscle damage,

soreness and delayed recovery but it is now well accepted that

the inﬂammatory stages are crucial for functional recovery of the

muscle to EIMD. The inﬂammation would ensure the removal of

tissue debris from the injured area and promote muscle repair

by activating muscle cells. Over the last decade, more studies

FIGURE 1 | Summary of the main speciﬁc features of eccentric contraction, its multi-target beneﬁcial effects and potential risks associated with unaccustomed

and/or maximal eccentric exercise.

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have focused on the implication of multiple immune cell types

interacting with the muscle and emphasized the undeniable role

of satellite cells for muscle regeneration following one bout of

eccentric exercise (Crameri et al., 2004; Paulsen et al., 2012).

Early accumulation of leukocytes, primarily neutrophils, has

been observed in micro-blood vessels of the damaged muscle,

as well as in the perimysium, immediately after exercise.

In case of moderate to severe EIMD, histological studies

have consistently shown that neutrophils inﬁltrate into the

muscle and accumulate in the damaged area from 1 and

24 h after eccentric exercise (Paulsen et al., 2010). It is

likely that secretion and/or passive release of chemoattractant

proteins due to modiﬁcations to membrane permeability are

involved in the recruitment of circulating inﬂammatory cells.

They initiate the pro-inﬂammatory stage through phagocytosis

and by releasing proteolytic enzymes (such as elastase or

myeloperoxidase) and reactive species. At later time points,

when neutrophils are cleared from muscle, pro-inﬂammatory

macrophages start to accumulate. This type of macrophages,

referred as M1, contribute to the phagocytosis of the damaged

tissue by secreting pro-inﬂammatory cytokines (e.g., TNF-α,

IL-6, and IL-1β) and secretory leukocyte protease inhibitor.

Tissue-resident monocytes may also become activated after

exercise, in addition to the leukocytes originating from the

blood circulation. Neutrophils and M1 macrophages interact

with each other to regulate the proinﬂammatory response

of muscle damage. Their inﬂux inside injured myoﬁbers

appears to be dependent on the magnitude of EIMD and

may lead to an exacerbation of the initial cellular alterations.

Conversely, M2 macrophages that appear later generally produce

anti-inﬂammatory cytokines and signaling molecules involved

in the muscle recovery and regeneration. Large variations

across healthy individuals are observed, some presenting

substantial leukocyte accumulation whereas others displayed

very little leukocytes invasion. Furthermore, the magnitude of

the inﬂammation response appears to be dependent on the

initial perturbations induced by the exercise. It is assumed

that minor perturbations result in a cell-signaling-mediated

adaptive response, whereas intense eccentric actions seem to

generate a more severe response leading to secondary damage

to myoﬁbers and increased risk of necrosis. While signiﬁcant

necrosis is observed after electrically stimulated contractions,

segmental myoﬁber necrosis may occur without aﬀecting the

whole myoﬁber, even in severe cases of EIMD. Interestingly,

the degree of leucocyte accumulation seems to be related to the

changes in force-generating capacity of the muscle (Paulsen et al.,

2010). Therefore, measuring the decline of muscular strength

following exercise, which is recognized as the best indirect marker

of EIMD, may inform on the status of the muscle. In contrast,

the level of leukocyte invasion into injured myoﬁbers is not

necessarily related to DOMS.

The muscle inﬂammatory response appears to intimately

coregulate with muscle regeneration. Indeed, additionally to their

immune functions, macrophages also participate to myogenesis

and contribute to the extracellular matrix remodeling.

M1 macrophages stimulate satellite cells proliferation whereas

M2 macrophages interact with diﬀerentiating satellite cells

(Paulsen et al., 2012). The latter can also promote general protein

synthesis within muscle ﬁbers. The replacement of macrophages

M1 to anti-inﬂammatory M2 macrophages is a key stage for

the transition from proinﬂammatory to anti-inﬂammatory

stages. This process is regulated by diﬀerent signals including

the phagocytosis of cell debris, IL10 and AMP-activated protein

kinase (Chazaud, 2016). While a large body of research has

primarily focused on neutrophils and macrophages, other

cell types interact with the muscle and are important in the

inﬂammation and muscle regeneration processes. These include

notably mast cells, T lymphocytes, eosinophils, ﬁbro-adipogenic

progenitors, and pericytes (Paulsen et al., 2012).

The inﬂammation and immune responses are mediated by

various growth factors and the actions of exercise-responsive

cytokines (i.e., IL-6, CCL2, and interferon-γ), pro-inﬂammatory

cytokines (TNF-α and IL-1β) and the anti-inﬂammatory cytokine

IL-10. Collectively, all these cytokines appear to activate myoblast

proliferation and some of them are involved in myoblast

diﬀerentiation (Peake J. et al., 2005). Interestingly, the satellite

cells activity is diﬀerentially aﬀected by the contraction mode

in human muscle following exercise of the same work load.

Resistance eccentric, but not concentric, exercise has been

shown to elicit the proliferation of satellite cells immediately

after exercise, suggesting that EIMD is the main stimulus for

activating the satellite cells pool (Hyldahl and Hubal, 2014;

Hyldahl et al., 2014).

The precise source of production for cytokines found in the

circulation during and after exercise is not well established.

Indeed, the cytokines can be produced not only by leucocytes, but

also by myoﬁbers and peri-tendinous tissue (Paulsen et al., 2010).

The term “myokines” has been introduced to refer to muscle

derived-cytokines and chemokines. Myokines are secreted by

the skeletal muscle in order to communicate with non-muscle

tissues and act as auto-, para- and endocrine mediators. These

might be molecular mediators which link muscle exercise and

the whole body physiology (Schnyder and Handschin, 2015).

While research to date has focused primarily on the biological

functions of the myokines in regulating metabolism, much less

attention has been made regarding their role in inﬂammatory

and adaptation to EIMD (Paulsen et al., 2010). Nevertheless,

studies investigating the cytokine responses to eccentric exercise

demonstrated increased activity of some cytokines such as MCP-1

and IL-10 after eccentric but not concentric exercise (Hyldahl and

Hubal, 2014). The anti-inﬂammatory cytokine IL-10 may attract

T lymphocytes, which activate muscle cell proliferation and

muscle regeneration. Systemic increase of IL-8 and upregulation

in intramuscular IL-8 mRNA expression and plasma levels after

downhill running and eccentric actions of the quadriceps has also

been reported (Hubal et al., 2008; Buford et al., 2009). IL-8 plasma

levels are also increased after eccentric muscle contractions,

but unchanged following concentric exercise. IL-8 is known to

attract primary neutrophils but this chemokine may also promote

neovascularization of muscle tissue through its association with

CXCR2 (Schnyder and Handschin, 2015). Some studies also

showed an increase in plasma concentration of IL-1ra and

G-CSF (granulocyte-colony stimulating factor) in the hours after

eccentric exercise (Peake J. et al., 2005; Peake J.M. et al., 2005).

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A large body of science has focused on IL-6. This myokine,

considered as one “exercise factor,” is regulated by exercise and

acts both locally within the muscle and on distal organs in an

endocrine-like fashion (Catoire and Kersten, 2015). IL-6 has

initially been characterized as a prototypical pro-inﬂammatory

cytokine by contributing to neutrophil mobilization and

activation and promoting impaired peripheral insulin resistance.

In contrast, anti-inﬂammatory properties of IL-6 have been

proposed later. Indeed, its exercise-induced systemic increase

generates the elevation of plasma level of several anti-

inﬂammatory cytokines (IL-1ra and IL-10) and inhibits the

production of the pro-inﬂammatory cytokine TNF-α (Pedersen

and Febbraio, 2008; Pedersen, 2012). Various cell types secrete

IL-6, including the skeletal muscle ﬁbers during and after

exercise. Alongside the systemic increase, IL-6 mRNA levels are

augmented in contracting muscle ﬁbers. IL-6 is considered as an

energy sensor of the muscle (Pedersen, 2012) since its secretion

from the exercising muscles increases glucose uptake and fatty

acid oxidation locally and improves insulin secretion, which

further increases glucose uptake into muscle ﬁbers. Hepatic

glucose delivery and fatty acid release from adipose tissue are also

stimulated supporting the maintenance of metabolic homeostasis

during exercise (Febbraio and Pedersen, 2002). Muscle derived

IL-6 was ﬁrst thought to be related to injury but “non-damaging

exercise” has been shown to lead to substantial IL-6 increase

(Croisier et al., 1999). Nevertheless, IL-6 contributes with TNF-α

and MCP-1 to muscle regeneration after EIMD by stimulating

the proliferation and diﬀerentiation of myoblasts (Schnyder and

Handschin, 2015). Moreover, the transforming growth factor-

beta is another cytokine involved in muscle recovery and

repair after muscle damage that regulates extracellular matrix

remodeling and promotes ﬁbrosis (Kim and Lee, 2017).

Delayed-Onset Muscle Soreness

Delayed-onset muscle soreness (DOMS) refers to unpleasant,

dull, aching pain, usually felt during palpation, contraction

or stretching of the aﬀected muscle. Such muscle soreness

typically appears 12–24 h after unaccustomed eccentric exercise,

peaks at between 24 and 72 h before progressively subsiding

and disappearing within 5–7 days post-exercise. Interestingly,

DOMS intensity is poorly correlated with other EIMD indirect

markers and seems thus not to reﬂect the magnitude of muscle

damage (Nosaka et al., 2002). Although DOMS is an extremely

common symptom, why DOMS occurs with a delay, and why

eccentric contraction but not shortening contraction induces

DOMS is not clearly understood. Several hypotheses have been

put forward to explain the mechanism of DOMS. These include

lactic acid release, spasm, connective tissue damage, muscle

damage, inﬂammation and oxidative stress (Hyldahl and Hubal,

2014). For many years, the most widely supported hypothesis was

that the biochemical, thermal and mechanical changes associated

with the inﬂammatory response sensitize small diameter muscles

aﬀerents (types III and IV) that may then be at the origin

of the sensation of muscle soreness (Friden and Lieber, 1992).

It was only in 2010 that Murase and coworkers provided new

insights into the molecular mechanisms of DOMS generation.

They highlighted bradykinin and nerve growth factor (NGF)

as important players in the development of DOMS following

eccentric contractions (Figure 1). Using a rodent model, they

demonstrated that a bradykinin-like substance released from

the muscle during eccentric exercise triggers the process of

muscular mechanical hyperalgesia by upregulating NGF through

B2 receptors in exercised muscle of rats. In humans, NGF has

been shown to be involved in the generation and potentiation

of pain following eccentric exercise (Nie et al., 2009). Another

pathway proposed to be involved in the development of

DOMS is the activation of the COX-2-glial cell line-derived

neurotrophic factor (GDNF) (Murase et al., 2013; Mizumura

and Taguchi, 2016). Similarly to NGF pathway, this agent likely

generates muscle mechanical hyperalgesia directly by stimulating

muscle nociceptors, or by binding to extracellular receptors.

While myoﬁbers micro-damage were believed to be necessary

to initiate inﬂammation and DOMS, some studies reported

mechanical hyperalgesia after eccentric exercises without any

signs of muscle damage. This supports the crucial roles of

NGF and GDNF in DOMS and suggests that the mechanical

hyperalgesia development may be associated with inﬂammation

in the extracellular matrix (Peake J. M. et al., 2017). NGF

and GDNF are also known to play a role in pathological pain

conditions and are increasingly recognized as active players in the

whole pain process and upregulated in ischemic skeletal muscle

(Turrini et al., 2002). NGF is increasingly regarded as an active

player in the whole pain process (McKelvey et al., 2013). Thus,

advances in the understanding of the mechanisms and cellular

origins of muscle soreness could lead to development of eﬀective

interventions for not only exercise-related muscle soreness, but

also common myalgia.

ECCENTRIC TRAINING-INDUCED

ADAPTATIONS

Molecular Aspects

The distinct features of the eccentric contraction compared

to other contraction modes are the source of speciﬁc training

adaptations. A signiﬁcant body of evidence suggests that

compared to concentric contractions, chronically performed

eccentric contractions promote greater gains in strength, muscle

mass and neural adaptations (Reeves et al., 2009; Roig et al.,

2009). The mechanisms responsible for these adaptations are

underlined by modiﬁcations in gene expression. Indeed the

process of exercise-induced adaptations in skeletal muscle

involves multiple signaling mechanisms initiating transcription

of speciﬁc genes that enable subsequent translation into a series

of new proteins (Coﬀey and Hawley, 2007). Several studies have

reported that eccentric and concentric actions activate distinct

muscular molecular pathways in humans (Kostek et al., 2007)

and in rats (Chen et al., 2002). It has been shown that eccentric

exercise triggers a progressive activation of genes responsible

for cellular growth and development, involved in muscular cell

hypertrophy processes. The expression levels of these genes

are more stimulated by eccentric actions than by isometric

or concentric actions (Chen et al., 2002; Barash et al., 2004;

Kostek et al., 2007), presumably due to the unique mechanical

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FIGURE 2 | Schematic representation of the potential mechanisms associated with eccentric exercise-induced muscle damage and involved in the development of

DOMS. BD, bradykinin; CK, creatine kinase; DOMS, delayed-onset muscle soreness; E–C, excitation–contraction; GDNF, glial cell line-derived neurotrophic factor;

IL, interleukin; NGF, nerve growth factor; ROS/RNS, reactive oxygen and nitrogen species; TNF, tumor necrosis factor.

stress placed on the eccentrically contracted muscles. For

example, in skeletal muscle, the eﬀect of eccentric training was

greater than concentric training for liver-type insulin-like growth

factor I and mechano-growth factor (positive regulators of

muscle growth) (Barash et al., 2004). Such modiﬁcations in gene

expression proﬁles are thought to be regulated by mechanical

signaling pathways involving proteins that are sensitive to the

mechanical status of muscle cell (i.e., Microtubules-Associated

Proteins or MAP proteins) (Hentzen et al., 2006). Transcriptome

analyses in eccentric-exercised muscles also revealed substantial

transcriptional activity related to the presence of leukocytes,

immune-related signaling and adaptive remodeling of the

intramuscular extracellular matrix until 96 h after exercise

(Neubauer et al., 2014). In comparison to concentric or isometric

contractions, eccentric contractions appear to upregulate muscle

cell activity and anabolic signaling pathway to a greater extent

(Douglas et al., 2017).

Speciﬁc Muscle Adaptations to

Chronic Eccentric Exercise

Because the eccentric contraction diﬀers from other contraction

types notably in terms of force generation, maximum force

produced and energy cost, it could provide diﬀerent stimuli

leading to distinct muscular and functional adaptations

(Figure 2) (Franchi et al., 2017a). A signiﬁcant body of evidence

have suggested the superiority of eccentric resistance training in

terms of muscular hypertrophy over concentric or conventional

strength trainings (Julian et al., 2018). Some studies also reported

earlier increments in muscle mass with eccentric-based resistance

training when compared with concentric training. However, the

ﬁndings appear extremely variable to clearly conﬁrm greater

gains in muscle mass following eccentric modalities (Julian

et al., 2018). Indeed, in their review, Franchi et al. (2014) draw

the conclusion that the changes in muscle size are similar

between eccentric and concentric training when matched for

load or work. A systematic review and meta-analysis about the

contribution of the diﬀerent muscle actions to muscle growth

showed a greater muscle mass gain with eccentric contractions

but the results did not reach signiﬁcance (Schoenfeld et al., 2017).

Nevertheless, taking into account the energy demand to produce

similar force or work, eccentric exercise may be considered as

more eﬃcient (Julian et al., 2018). Interestingly, contraction type

tends to induce a region-speciﬁc hypertrophy. Greater increase

in distal muscle size has been observed following eccentric

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training, while concentric training favors median-muscle

hypertrophy (Franchi et al., 2014). In addition, the hypertrophic

responses to eccentric versus concentric contractions might be

obtained by diﬀerent structural adaptations mediated by distinct

myogenic and molecular responses. While both training regimes

appeared to increase muscle fascicle length and pennation

angle (Blazevich et al., 2007), conventional strength training

would increase pennation angle more than eccentric training.

In contrast, eccentric-only resistance training seems to favor

fascicle length increase (Reeves et al., 2009), with the implication

that eccentric training is able to shift the optimum of the

length-tension relationship to longer muscle length (Hoppeler,

2016). This muscle architectural change appears thus particularly

interesting for injury prevention and athletic performance

(Brughelli and Cronin, 2007). Regarding muscle thickness,

similar increases have been observed with both training modes.

There are evidence that eccentric training promotes signiﬁcantly

greater increase in muscle strength, whereas the diﬀerences

in isometric and concentric measures seems less signiﬁcant

(Roig et al., 2009). Findings also showed that the increase in

eccentric strength after eccentric training is greater than the

gain in concentric strength after concentric training (Vikne

et al., 2006). The systematic review of Douglas et al. (2017)

also reported mode-speciﬁc strength increase and revealed that

greater overall strength increases can be achieved after eccentric

training than concentric or traditional training. Furthermore,

in comparison with concentric exercise, eccentric actions have

been reported to induce a greater cross-education eﬀect. Only

few studies examined changes in muscle power. Performance in

actions involving muscle power or stretch-shortening cycle (such

as vertical jump) appeared to be improved to a greater extent

with eccentric training compared with concentric or traditional

resistance training (Liu et al., 2013; Douglas et al., 2017).

The Repeated-Bout Effect (RBE)

Skeletal muscle exhibits an intriguing plasticity to repeated

bouts of eccentric exercises. Among the adaptations speciﬁcally

triggered by the eccentric contraction, some contribute to the

RBE, aiming thus to protect muscle against EIMD. A large

number of theories have been proposed to explain the RBE,

suggesting a multifactorial origin of this adaptive process.

Potential adaptations have been categorized as (Lindstedt et al.,

2001) neural, (Abbott et al., 1952) mechanical and (LaStayo et al.,

2003b) cellular theories (McHugh et al., 1999a; McHugh, 2003).

However, although many studies have attempted to elucidate the

mechanisms behind the RBE, a uniﬁed theory is not yet available.

According to the neural theory, the EIMD results from

the high mechanical stress imposed on a small number of

active muscle ﬁbers during intense eccentric contractions.

Although not commonly accepted, this theory also supports

a preferential recruitment of fast-twitch motor units during

eccentric contractions to explain the higher susceptibility to

disruption of the fast muscle ﬁbers. Therefore, it has been

postulated that changes in neural activation may contribute

to reduce subsequent myoﬁbrillar damage (McHugh, 2003).

Suggested neural adaptations involve improved motor units

(MUs) synchronization and activation of a large pool of MUs,

mainly by recruiting a greater number of slow-twitch ﬁbers

(Warren et al., 2000; Chen, 2003; Starbuck and Eston, 2012). Such

mechanisms would allow a better distribution of the workload

over a greater number of active muscle ﬁbers in repeated bouts

(Nosaka and Clarkson, 1995). The fast-setting adaptations but

also the existence of contralateral protective eﬀect (Howatson

and van Someren, 2007; Starbuck and Eston, 2012; Hody et al.,

2013b) support the contribution of neurophysiologic processes

in the RBE. Indeed, some studies have reported that an initial

bout of eccentric exercise in one limb provides protection from

the symptoms of EIMD during a second eccentric bout in the

contralateral limb. Nevertheless, the magnitude of protection

in the contralateral limb is lower than that observed in the

ipsilateral limb, indicating that neural adaptations cannot entirely

explain the RBE (Howatson and van Someren, 2007). Moreover,

the demonstration of RBE with electrically stimulated eccentric

contractions (Black and McCully, 2008) suggests that the RBE

can occur independently of neural adaptations and involves thus

a peripheral and/or muscular adaptation.

The mechanical origin of initial muscle damage has led

authors to suggest that changes in mechanical properties of the

musculoskeletal system could render the muscle more resilient

to EIMD. With respect to this hypothesis, both the passive

and dynamic stiﬀness of the muscle-tendon complex has been

shown to increase after eccentric training (Howell et al., 1993;

Reich et al., 2000). These modiﬁcations have been, respectively,

attributed to an increase in intramuscular connective tissue

improving the ability to withstand myoﬁbrillar stress and to

a reinforcement of intermediate ﬁlament system, in charge of

maintaining the alignment and structure of the sarcomeres

(i.e., titin, desmin) (McHugh, 2003). In agreement with the

reorganization of cytoskeletal proteins, the level of certain

structural proteins, such as desmin, was found to increase in

the days following eccentric exercise (Feasson et al., 2002; Lehti

et al., 2007). This suggests that muscle-speciﬁc cytoskeletal

remodeling could play a role to protect from future sarcomere

disruption. Desmin, the major protein of the muscle intermediate

ﬁlament, would act as mechanical integrator for the repair of

the ﬁlaments (Yu et al., 2002). Its reinforcement secondary to

transcriptional upregulation may provide mechanical protection

from future sarcomere disruption (Peters et al., 2003). However,

some studies showing that stiﬀer muscles are more prone to

damage questioned the mechanical theory (McHugh et al.,

1999b). Moreover, desmin knockout (KO) mice have been

found to exhibit less exercise-induced than wild-type mice (Sam

et al., 2000). This ﬁnding was, however, imputed to more

compliant muscles of KO mice. Recent works have suggested

that in addition to their function of structural support to

the cell, the intermediate ﬁlaments may play an active role

in biological processes such as signaling, mechanotransduction

and gene regulation. The mechanisms behind these processes

are not well understood. Desmin, which is responsible for

transmission of stress among myoﬁbrils appears to be required

for the maintenance of myoﬁber alignment, nuclear deformation,

stress production and JNK-mediated stress sensing (Palmisano

et al., 2015). Growing evidence supports the role of the

skeletal muscle intermediate ﬁlaments as a stress-transmitting

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and stress-signaling network. Notably, cytoskeletal proteins help

mitochondria not only in their movement and proper cellular

positioning, but also to maintain their biogenesis, morphology,

function, and regulation of energy ﬂuxes. The functionality of

these cytoskeletal proteins may thus inﬂuence the mitochondria

functions, including the regulation of Ca

signals and apoptosis

(Mado et al., 2019). Remodeling of the intermediate ﬁlaments

network may also impact cell migratory behaviors important to

development (Sanghvi-Shah and Weber, 2017).

Another group of theories explaining the RBE relies on

cellular adaptation. Given the focal feature of muscle damage,

speculation has been made that the muscle becomes more

resistant to EIMD thanks to the removal of stress-susceptible

ﬁbers or sarcomeres resulting from the initial eccentric bout

(Armstrong, 1984; Newham et al., 1987). However, this is

inconsistent with the fact that the initial bout does not have to

cause appreciable damage to confer a protective eﬀect. Several

works provided evidence that eccentric exercise promotes an

increase in series sarcomeres (Lynn and Morgan, 1994; Yu et al.,

2004). Such longitudinal addition of sarcomeres is thought to

contribute to the protective eﬀect as it would avoid the sarcomere

stretching beyond their overlap and thus, their disruption. The

sarcolemma and sarcoplasmic reticulum would also become

stronger following the initial bout of eccentric exercise (McHugh,

2003). This may limit perturbations of calcium homeostasis and

thus, may prevent the calpain activation and the degradation

of cytoskeletal proteins. The reduced calpain activity could

then explain the attenuation of mitochondrial dysfunction

following chronic exposure of eccentric exercise. Other potential

adaptations such a decreased susceptibility to calcium-induced

mPTP (mitochondrial permeability transition pore) opening or

upregulation of heat shock proteins, in particular Hsp70, may also

be contribute to protect mitochondrial function (Rattray et al.,

2013). In addition, changes in the inﬂammatory response, such as

a reduced activation of the monocytes and neutrophils, have been

described after repeated eccentric bouts and may also be related

to the RBE (Pizza et al., 1996). Nevertheless, whether adaptation

in the inﬂammatory process is the cause or a consequence

of reduced muscle damage is not elucidated. Adaptation

may also rely on the monocyte chemoattractant protein 1

(MCP-1), a chemokine involved in activation and attraction of

inﬂammatory cells. Indeed, MCP-1 is dramatically overexpressed

at the transcript level after a single bout of eccentric exercise and

it appeared even more upregulated after a second bout (Hubal

et al., 2008). Authors have thus suggested that MCP-1 enhances

muscle recovery after a repeated bout of eccentric exercise via

improved signaling between macrophages and satellite cells.

Other chemokines may contribute to the protective adaptation

to exercise-induced muscle damage. Upregulation of CCL2 and

a decreased of NF-kB DNA-binding activity occur following

repeated bouts of eccentric exercise. These observations supports

the hypothesis that the immune response becomes more eﬃcient

to promote the regeneration of muscle tissue after an initial

bout of eccentric exercises, notably through enhancement in

inﬂammatory cell inﬁltration into the muscle and myoblast

proliferation (Peake J. et al., 2005). Furthermore, a remodeling

of the surrounding extracellular matrix might also occur during

the RBE. A strengthening of the extracellular matrix such as

an improved integrin support may help to recover faster after

eccentric contractions (Hyldahl et al., 2015).

Other potential cellular adaptations include increased protein

synthesis, adaptation in the excitation-contraction coupling and

increased stress proteins (i.e., heat shock proteins) (McHugh,

2003). In particular, the role of heat shock proteins (HSPs) in

protection against muscle damage constitutes an exciting new

area of research. The small HSPs (sHSPs) named HSPB1 (Hsp27)

and alphaB-crystallin, seem to play important roles in cellular

adaptation as they have been implicated in the chaperoning of

unfolded proteins, the stabilization of the cytoskeleton as well

as in the regulation of the cellular redox state and inhibition

of apoptosis (Orejuela et al., 2007). Following one bout of

eccentric exercise, the sHSPs translocate from the cytosol to the

cytoskeletal/myoﬁbrillar compartment, presumably to stabilize

and protect the myoﬁbrillar ﬁlament organization (Paulsen et al.,

2007, 2009; Frankenberg et al., 2014). Such an observation was

not found after concentric exercise (Frankenberg et al., 2014).

AlphaB-crystallin interacts with desmin intermediate ﬁlaments

and, Hsp27, together with alphaB-crystallin, has been suggested

to interact with various microﬁlaments (Orejuela et al., 2007).

These data strongly support the idea that alphaB-crystallin and

Hsp27 are crucial for the maintenance and the remodeling of

myoﬁbrillar structures. Therefore, in line with the reinforcement

of the cytoskeletal/myoﬁbrillar structures, appropriate adaptation

in the protection systems of HSPs might be important as

well (Paulsen et al., 2007). Moreover, because the HSPs are

involved in the development of stress tolerance against several

stressful insults, it is likely that the HSPs response elicited

by an initial damaging bout bestows resistance to a second

potentially damaging exercise. Only few studies investigated the

HSPs response to repeated bouts of eccentric exercise. Paulsen

et al. (2009) revealed that two bouts of maximal eccentric exercise

separated by 3 weeks resulted in comparable increased levels of

HSPs in the cytoskeletal fraction, despite less damage inﬂicted

during the second bout. The large amount of Hsp27, alphaB-

crystallin, and Hsp70 in the cytoskeletal compartment after the

repeated bout suggests that a more eﬃcient translocation of

these HSPs is plausibly a mechanism behind the RBE. Similarly,

Thompson et al. (2002) reported a similar relative increase of

Hsp27 and Hsp70 2 days after the ﬁrst and second eccentric bouts,

but, intriguingly, the basal levels of these HSPs appeared to be

lower before the second bout. This ﬁnding casts doubt on the

HSPs as important players in the RBE. Contrary to these ﬁndings,

results from a study by Vissing et al. (2009) did not point out a

role for the HSPs in reducing EIMD, as they observed a blunted

translocation of HSPs after the second bout. In this latter study,

the low degree of muscle damage inﬂicted during the exercise

and/or the long duration between bouts (8 weeks) could explain

the lack of HSPs movement following the second bout. Future

studies appear thus to be necessary to delineate the HSPs response

after repeated eccentric bouts.

Finally, using a proteomic approach, a short isokinetic

eccentric training in human quadriceps was found to induce

proteome modiﬁcations that suggest an isoform shift in ﬁber

type components (Hody et al., 2011). Indeed, a decreased

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expression of several glycolytic enzymes coupled with a lower

expression of the fast isoforms of some contractile and structural

proteins was observed after ﬁve sessions of submaximal eccentric

contractions. Adaptation in the muscle ﬁber typology following

eccentric training was further supported by a study in mice.

This highlighted signiﬁcant changes in the size and number

of muscle ﬁber types following eccentrically biased trained in

comparison with untrained or concentrically biased trained

mice: the eccentric training speciﬁcally resulted in an increased

proportion of slow and fast oxidative muscle ﬁbers (Hody et al.,

2013a). Nevertheless, whether a shift to a more oxidative muscle

phenotype is really involved in protection against EIMD is still a

question to resolve.

MULTIPLE APPLICATIONS OF

ECCENTRIC TRAINING

Eccentric training has sparked a growing interest over the

last decade, particularly in light of the emerging health-

related beneﬁts of improved muscle mass. Moreover, because

a greater volume of exercise can be done at less metabolic

and cardiorespiratory cost, eccentric muscle work constitutes

a promising training strategy, not only to improve athletes’

performances, but also to help maintain or restore the exercise

capacity and quality of life in individuals with reduced tolerance

for physical activity (i.e., the elderly or patients with chronic

disabilities) (Gault and Willems, 2013; Hyldahl and Hubal, 2014;

LaStayo et al., 2014). The lower perceived exertion to perform

eccentric exercises helps to increase the adherence of patients to

exercise programs. As eccentric contractions have traditionally

been associated with muscle damage, the prescription of eccentric

training programs in clinical practice has been discouraged

for a long time. Nowadays, it is well accepted that when

the duration, frequency and intensity of the eccentric training

sessions are progressively increased, symptoms of damage can

be minimized and even avoided (Croisier et al., 1999; Chen

et al., 2013). Additionally, it is now accepted that neither muscle

damage nor inﬂammation are prerequisites for stimulating

positive muscle adaptations as protection against EIMD or

increased muscle mass (LaStayo et al., 2007). Eccentric training

interventions are thus considered as a safe and suitable alternative

to traditional resistance exercise. Before discussing the numerous

applications of eccentric training, it should be mentioned that

the identiﬁcation of its speciﬁc eﬀects in comparison to the

other training modalities remain diﬃcult due to methodological

reasons. First, the training programs used in several studies

involved usual daily movements that do not isolate eccentric

and concentric contractions. Secondly, a limited number of

studies employed an appropriate calibration of the eccentric

and concentric exercises, making conclusive comparison between

the contraction modes impossible. Since they imply diﬀerent

metabolic cost for the same mechanical work, eccentric and

concentric exercises must be matched for similar mechanical

output, metabolic rate or oxygen consumption level, or similar

total training load. Additionally, the techniques and equipment

to perform eccentric exercises is often sophisticated, require

speciﬁc experience and may represent ﬁnancial constraints. These

reasons may contribute to the few number of studies comparing

eccentric training with other modalities and the diﬃculty to draw

deﬁnitive conclusions (Julian et al., 2018).

Competitive Sports

While few studies have been devoted to the eﬀects of eccentric

training in elite athletes compared to untrained subjects, the

systematic inclusion of eccentric-based protocols into training

programs is recommended for most competitive sports for

performance enhancement or injury prevention purposes (Isner-

Horobeti et al., 2013; Vogt and Hoppeler, 2014). Indeed, because

of its distinct characteristics, eccentric training modalities can

further enhance maximal muscular strength and optimize

improvements to power, optimal muscle length for strength

development, as well as coordination during eccentric tasks

(LaStayo et al., 2003a). Eccentric training may also be especially

eﬃcient in enhancing speed performance or in rebound activities

such as jump (Franchi et al., 2017b; Chaabene et al., 2018).

This has notably been demonstrated in basketball players. Those

subjected to eccentric training for 6 weeks exhibited a signiﬁcant

improvement in jumping height of 8% while the performance

of the players that performed traditional weight-lifting was

unchanged (Lindstedt et al., 2002). A change in titin protein

isoform has been proposed to explain the increased stiﬀness of

the muscle-tendon unit and enhanced recovery of elastic strain

energy (Hoppeler, 2016). These functional adaptations in skeletal

muscles are based on increases in muscle mass, fascicle length,

number of sarcomeres, and cross-sectional area of type II ﬁbers.

In terms of injury prevention, the isokinetic assessment of muscle

function, in particular through the eccentric mode, appears to

be of great importance for detecting athletes at high risk of

injuries before the start of the season (Croisier et al., 2002;

Forthomme et al., 2013). Moreover, preventive interventions

with controlled eccentric exercises have been shown to decrease

the risk of hamstring injury in professional soccer players

(Croisier et al., 2008) or of shoulder pain in volleyball players

(Forthomme et al., 2013).

Rehabilitation

Over the last 20 years, eccentric muscle actions have been

frequently integrated in the treatment of several pathologies of

the locomotor system (Croisier et al., 2009). In particular, chronic

eccentric exercise has become a mainstay in the treatment

of tendinopathies mainly of the Achilles, patellar and lateral

epicondylar tendonitis (Croisier et al., 2007; Hoppeler and

Herzog, 2014; Kjaer and Heinemeier, 2014). To justify the

relevance of eccentric exercise for strengthening tendon tissues,

a stimulating impact of such exercise on collagen synthesis and

an increase in blood ﬂow around tendon cells after eccentric

actions have been proposed (Guilhem et al., 2010). Eccentric

intervention has also been shown to be safe and eﬀective after

anterior cruciate ligament reconstruction (ACLR). The studies of

Gerber et al. (2007, 2009) reported superior short and long-term

results in strength, performance and activity level after surgery

when eccentric exercise is part of the rehabilitation after ACL-R

in comparison to standard rehabilitation programs. Otherwise,

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ipsilateral eccentric training has been demonstrated to increase

muscles’ strength in the contralateral homologous muscle group,

and this in a greater extent than concentric training (Higbie et al.,

1996; Hortobagyi et al., 1997). Thus, implementing unilateral

eccentric contractions in rehabilitation programs could improve

the muscle function of the opposite injured limb without it

being solicited.

Sarcopenia

Given the ever-increasing aging population, the development

of strategies to improve the quality of life of the elderly has

become a major concern. One of the most evident and disabling

consequences of aging is sarcopenia, a process characterized

by a progressive and steady loss of lean skeletal muscle mass.

Muscle loss is also associated with an increase in intramuscular

fat and connective tissue, a reduction in muscle strength, in

addition to cardiovascular dysfunction reducing aerobic capacity

(Gault and Willems, 2013). Such changes contribute to a

decline in functional independence and severely compromise

the function, quality of life, and life expectancy in older

individuals. Multiple lines of evidence suggest that exercise

training can prevent or reverse muscle aging. Indeed, studies

comparing muscle characteristics of highly trained young and

senior athletes demonstrated that trained subjects can maintain

and improve muscle function regardless of their age (Roig et al.,

2008; Dickinson et al., 2013). However, the implementation of

conventional resistance training programs in the elderly may be

hampered by the diﬃculty of such programs as reduced initial

levels of force and cardiovascular dysfunction are frequent in

old adults. Conversely, eccentric training programs can massively

overload the muscular system with a low cardiopulmonary

stress. Interestingly, numerous studies reported that older

individuals exhibit a relatively preserved capacity of producing

eccentric strength. Indeed, when compared to concentric or

isometric strength, the magnitude of the age-related decline in

eccentric strength is less pronounced. This provides an additional

advantage for eccentric exercises to initiate resistance training

and rehabilitation programs (LaStayo et al., 2003b; Roig et al.,

2010). In addition to the suitability of eccentric training in old

individuals, it is important to emphasize that resistance training

with eccentric contractions induces greater beneﬁcial eﬀects than

concentric training to improve mobility and independence of

the elderly. As in young individuals, high-intensity eccentric

resistance training has been shown to be more eﬀective than

concentric training in increasing muscle strength and mass in

older adults (LaStayo et al., 2003a; Reeves et al., 2009). Other

appreciable beneﬁts resulting from eccentric training in old

individuals are the improved ability to complete functional tasks

and the decreased risk of fall (Gault and Willems, 2013). LaStayo

et al. (2003a) demonstrated that using eccentric modality in

very frail elderly (mean age, 80 years) was more eﬃcient to

reverse sarcopenia and its related functional limitations than

traditional weight training. Indeed, the elderly who performed

10–20 min of eccentric resistance exercise 3 times per week

over 11 weeks showed signiﬁcant improvements in strength

(60%), balance (7%), stair descent (21%) abilities and a reduced

risk of fall. These positive outcomes were not found in the

elderly subjects submitted to traditional resistance exercises.

Additionally, the subjects of the eccentric group reported the

training to be relatively eﬀortless. Besides resistance training,

eccentric endurance exercise involving large muscle groups (ECC

cycling, downhill treadmill walking, and stepping) seems to

be particularly convenient for the elderly (in particular for

frail elderly). This training modality minimizes the substantial

mechanical stress on single joints occurring during resistance

training and provides beneﬁts for strength, muscle mass and

potentially aerobic adaptations (Gault and Willems, 2013;

LaStayo et al., 2014). The study of Mueller et al. (2009) compared

the eﬀects of a moderate load eccentric exercise on an eccentric

ergometer to a conventional resistance exercise training. Both

trainings were carried out for 12 weeks with 2 sessions per

week. A signiﬁcant increase in maximal isometric strength (8.4%)

was observed only for the eccentric group (Mueller et al.,

2009). Improvements in body composition characterized by a

decrease in intramyocellular lipid content concomitantly with

total body fat have also been observed in the elderly after

12 weeks of eccentric ergometer training (Mueller et al., 2011).

In contrast, tight lean mass increased similarly after both training

modalities. Interestingly, the gain in muscle mass in the elderly

following eccentric training was not paralleled by an increase in

muscle ﬁber cross-sectional area (hypertrophy) as observed with

traditional exercise training (Mueller et al., 2011). Muscle growth

after eccentric training thus seem to occur by the addition of

sarcomeres in series or by hyperplasia. While available evidence

suggest that eccentric training protocols are well tolerated in

elderly individuals, it should kept in mind that old adults show

an increased vulnerability to exercise-related muscle damage.

Indeed, biopsies from the human m. vastus lateralis immediately

after a bout of eccentric cycling showed disorganization of

sarcomeres, with a higher percentage of disorganization in

older (59–63-years) compared to younger adults (20–30-years)

(Manfredi et al., 1991). Therefore, careful and safe progression of

the intensity of eccentric training is thus strongly advised when

initiating eccentric programs in the elderly.

Chronic Diseases

Musculoskeletal dysfunction is relatively common in patients

with chronic conditions such as chronic obstructive pulmonary

disease, chronic heart failure or stroke (Hyldahl and Hubal,

2014). Although the exact etiology of the muscle function

decline in these patients is not yet clear, it is believed that

the lack of physical activity contributes at least to some

of the deleterious changes in muscle function (Roig et al.,

2008). Moreover, the ability of exercise to maintain mobility

and minimize muscle wasting in most people with chronic

conditions is commonly accepted. Until now, only few studies

explored the use of eccentric-biased programs in persons with

chronic health conditions. Nevertheless, current evidence exists

regarding the eﬀectiveness and safety of eccentric exercise in

restoring musculoskeletal function in patients with diﬀerent

chronic conditions. For instance, compared to conventional

training programs, judicious eccentric-based protocols result in

greater strength gains and enhancement of functional capacity

in cancer survivors, Parkinson disease patients or total knee

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Hody et al. Eccentric Exercise

replacement patients (Hyldahl and Hubal, 2014). However,

such favorable eﬀects were not observed in individuals with

multiple sclerosis (Hayes et al., 2011). Studies exploring the

use of resistance training in individuals recovering from a

stroke revealed that eccentric contractions were more eﬀective

for improving neuromuscular activation, strength, and walking

speed than concentric contractions (Engardt et al., 1995; Clark

and Patten, 2013). Since eccentric training seems to provide

greater central neural adaptation than concentric modes of

exercise, the use of eccentric exercise may be particularly

eﬀective for patients with central nervous system diseases. The

physiologic characteristics of eccentric contraction (attenuated

cardiopulmonary stress, low metabolic cost) seem to be well

suited for their incorporation into the revalidation of patients

intolerant to intense cardiac and respiratory eﬀorts (i.e., patients

with heart disorders or lung pathologies) (Meyer et al., 2003; Roig

et al., 2008). Eccentric training has been suggested to attenuate

reductions in arterial compliance, thus potentially limiting the

risks commonly associated with resistance training in patients

with coronary disease (Okamoto et al., 2006). Steiner et al. (2004)

compared concentric and eccentric training at similar heart

rate (85% of HR) in patients suﬀering from cardiac problems.

Training was carried out 3 times per week during 8 weeks,

with a progressive increase of the exercise intensity the ﬁrst

5 weeks. The authors showed a signiﬁcant gain in muscle torque

following the eccentric training. Both training modalities induce

a small 3% increase in leg muscle mass but leg and whole

body fat mass appeared to decrease only in patients trained

eccentrically. Interestingly, despite working at fourfold higher

mechanical loads, the eccentric group did not show diﬀerent

changes in cardiovascular variables (such as heart rate, mean

arterial pressure, or vascular resistance) than the concentrically

trained subjects (Meyer et al., 2003). Collectively, all studies

reported eccentric exercise to be a safe training modality for

patients with various cardiac conditions.

Eccentric exercise may also be useful in the prevention or

treatment of metabolic diseases given its rapid and favorable

eﬀects on health related parameters (Roig et al., 2008;

Paschalis et al., 2010; Isner-Horobeti et al., 2013). For instance,

eccentric training is more eﬀective to improve glucose tolerance

than concentric training. Additionally, Paschalis et al. (2010)

demonstrated that a weekly bout of intense eccentric exercise –

and not concentric exercise – is suﬃcient to improve health risk

factors. They found that only 30 min of eccentric exercise per

week for 8 weeks markedly increased resting energy expenditure

and lipid oxidation as well as decreased insulin resistance

and blood lipid proﬁle. The study of Marcus et al. (2008)

compared the eﬀects of a 16-week aerobic exercise training

alone to aerobic exercise combined with moderate load eccentric

exercise in diabetes type 2 patients. While glycemic control and

physical performance were similarly improved in all patients, the

improvements in tight lean mass and body mass index were larger

when eccentric exercise was performed.

In regard with muscular dystrophy pathology, no human

study investigated the potential eﬀects of eccentric training in

this disease. It is likely that eccentric contractions may accelerate

the degenerative process given that the degenerative nature of

dystrophic muscle can partially be accounted for by exhaustive

regenerative cycles (Hyldahl and Hubal, 2014). Nevertheless,

some recent animal studies indicate a favorable adaptation to

moderate exercise in dystrophic animals (Lovering and Brooks,

2014). In fact, despite the increased vulnerability of dystrophic

(mdx) muscles to eccentric contractions, young mdx mice were

found to recover from and adapt more quickly to EIMD than

wild-type mice (Ridgley et al., 2009; Call et al., 2011). However,

such increased regenerative capacity was lost in older animals

(Carter et al., 2002) and it is still unclear whether an eccentric-

based training program would be helpful or detrimental to the

long-term health of the muscle.

Notwithstanding recent evidence demonstrate the beneﬁts of

eccentric training interventions in several ﬁelds, there is a real

need to further study the physiology of eccentric contraction.

Indeed, it is still unclear whether this high speciﬁcity of

eccentric training adaptations compromises the transferability

of strength gains to more functional movements (Roig et al.,

2010). Moreover, long-term implications of eccentric training

in old individuals or in patients with chronic diseases should

be explored in more details. Likewise, further investigations

are required to optimize parameters as intensity, duration, and

modes of eccentric training leading to the favorable eﬀects on

muscle performance, health and quality of life.

PRACTICAL CONSIDERATIONS

Eccentric actions can be integrated in diﬀerent types of

muscle training. Plyometric exercises, such as drop jump, is

frequently used to improve speed and jumping ability in athletes.

The literature recommends speciﬁc habituation training and

knowledgeable supervision due to the inherent risk of injuries

in such exercises (Hoppeler, 2016). Eccentric based resistance

training, characterized by high muscle loads at low metabolic

cost, has been increasingly prescribed for individuals with

a centrally limited exercise tolerance (LaStayo et al., 2014).

However, in most patient populations, the use of high mechanical

loads may constrain their adherence to resistance muscle

training. Therefore, the new modality “moderate load eccentric

exercise” represents an attractive choice in various medical

conditions (Hoppeler, 2016). Over the last decades, various

motorized ergometers or similar devices allowing safe and

controlled application of eccentric loads, have been developed for

rehabilitation and performance purposes.

The prescription of eccentric muscle training require speciﬁc

experience. Practitioners must respect fundamental precepts

and consider important safety considerations concerning the

applications of eccentric muscle training, especially during

the initial implementation phase. Exercise professionals should

be aware of the potential detrimental eﬀects of eccentric

contractions as well as the ways to prevent their occurrence.

Nowadays, it is well accepted that repeated exposure to eccentric

exercises confers protective adaptations against potential further

damage (McHugh, 2003; Nosaka and Aoki, 2011). Even if

the magnitude of this “repeated-bout eﬀect” appeared larger

if the initial eccentric bout involved high workloads, this

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Hody et al. Eccentric Exercise

strategy could be problematic, especially for those undergoing

rehabilitation or elite athletes. Indeed, DOMS and the functional

consequences associated with EIMD may frequently disturb the

progress of rehabilitation and/or training programs. Moreover,

the uncomfortable sensations may discourage people to continue

exercise training. Therefore, an initial phase consisting of

submaximal eccentric muscle actions with incremental loading

over multiple sessions should be used to introduce individuals

to eccentric muscle training (LaStayo et al., 2003b). Flann et al.

(2011) demonstrated that a 3-week gradual “ramp up” eccentric

protocol was eﬀective at promoting muscle hypertrophy in

the absence of demonstrable markers of muscle damage. In

clinical interventions, the progressive ramping eccentric protocol

typically starts with load of 50–75 W to reach the target

training load of 400–500 W. Higher loads, over 1,200 W, can

be achieved in competitive athletes (Hoppeler, 2016). A period

of 2–4 days between the exposure stimulus and progressively

higher levels of loading has been suggested as optimal (Hoppeler,

2016). Guidelines to design ramping protocols in rehabilitation

conditions are described in more details by LaStayo et al. (2014).

The exercise duration generally increases from 5–10 min to

20–30 min over the sessions. When using higher load trainings,

four bouts of 5 min seems to be equally eﬀective and less tiring

for subjects (Steiner et al., 2004; Vogt and Hoppeler, 2014).

A training frequency of two sessions per week seems to be the

lower limit to induce measurable gains (Mueller et al., 2009).

When conceiving eccentric interventions, practitioners should

also take into account the parameters aﬀecting the extent and

duration of EIMD and/or slower recovery. Exercises performed at

high vs. low eccentric torque, at long vs. short muscle length and

increasing numbers of eccentric contractions appear to result in

more severe EIMD (Nosaka and Newton, 2002). Skeletal muscles

do not display the same vulnerability to EIMD. The upper limb

muscles appear mostly more aﬀected than lower limb muscles

and the knee ﬂexors more than the knee extensors (Chen et al.,

2011). The untrained status, genetic variations, aging and chronic

diseases are other factors increasing the severity of potential

EIMD (Tidball, 2011; Gault and Willems, 2013; Baumert et al.,

2016). Special attention should thus be given to these populations

when establishing the initial eccentric exercise prescription in

rehabilitation settings.

Even if trained athletes are generally less aﬀected by EIMD

than untrained people when submitting to the same eccentric

protocol, they might not escape to the detrimental eﬀects of

eccentric contractions in some circumstances. They might be

particularly vulnerable to EIMD at the start of the season,

or when they return to competition after injury or following

an unaccustomed eccentric session (Cheung et al., 2003). The

occurrence of EIMD associated with unaccustomed eccentric

exercise could be problematic in athletes because of the

associated negative consequences on locomotor biomechanics

and sport performance within the short term (Cheung et al.,

2003; Assumpcao Cde et al., 2013). Moreover, when athletes

suﬀered from DOMS, they are frequently unable to train at

their maximal intensity which can compromise the quality

of the training programs. Even if the negative functional

consequences of EIMD are transitory, it seems important to

avoid their onset even in healthy athletes. If EIMD have not

been avoided, it is recommended not to perform high intensity

exercises, particularly explosive eﬀorts. Indeed, the risk of

injuries such as muscle tears or ligament rupture has been

shown to increase due to the disturbed muscle function and

mechanical fragility. Accordingly, it should be kept in mind

that even when muscle hyperalgesia is resolved, a decrease in

muscle function may persist. Care must thus be exerted in

the days following an episode of DOMS (Damas et al., 2016).

When experiencing EIMD, stretching should also be avoided

since it could interfere with recovery. Since EIMD triggers

inﬂammation response, some practitioners have used non-steroid

anti-inﬂammatory drugs (NSAIDs) in an attempt to attenuate

the clinical symptoms (Paulsen et al., 2012). Nevertheless, studies

demonstrated that reducing or blocking potential inﬂammation

response may negatively perturb the muscle cell activity and

hinder the hypertrophy and regenerative processes (Mackey

et al., 2007). Therefore, NSAIDs should be avoided in healthy

subjects (Paulsen et al., 2012). Contrary to this, evidence suggests

that NSAIDs may be beneﬁcial for subjects characterized by

a low-grade systemic inﬂammation contributing to sarcopenia

(Bautmans et al., 2005; Rieu et al., 2009). In the elderly or in

individuals with chronic disease, the use of NSAIDs may help to

maintain muscle mass (Rieu et al., 2009).

CONCLUSION

The study of eccentric contraction is no longer conﬁned to

muscle physiology and sport sciences but is becoming central

in clinical medicine and is likely to expand in the near future.

Indeed, due to its unique neural, mechanical and metabolic

properties, the eccentric mode has gained a growing interest in

several ﬁelds. In addition to its eﬃciency in sports performance

and rehabilitation, the eccentric training interventions constitute

an attractive strategy to prevent muscle wasting in sarcopenia

or in many chronic diseases. Increasing evidence also support

the beneﬁcial eﬀects of eccentric exercises on body composition

and other health-related parameters, making this contraction

mode a promising tool for various patient populations. However,

unaccustomed eccentric exercise is well known to induce muscle

damage that manifests by a range of clinical symptoms including

DOMS and decreased muscle function. Up to now, there is no

equivocal therapeutic approach allowing a signiﬁcant attenuation

in the symptoms of damage. Conversely, it has been clearly

demonstrated that repeated exposures to eccentric actions with

progressively increasing loads can prevent the occurrence of

muscle damage or DOMS.

FUTURE PERSPECTIVES

Although the eccentric contraction has received more attention

over the last decade, many questions remain unanswered with

regard to both the initial damaging response to unaccustomed

eccentric contraction and the subsequent adaptations. Further-

more, the mechanisms behind the protective eﬀect conferred

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Hody et al. Eccentric Exercise

by a repeated eccentric bout are still in great part speculative.

Yet, the numerous practical applications of eccentric exercise

in sports, rehabilitation and pathological conditions justify the

need to elucidate the mechanisms underlying the acute and

chronic eﬀect of eccentric exercise on the skeletal muscle.

In addition, a better knowledge of the transient eccentric induced

damage and subsequent adaptations on a mechanistic level

may help to further understand the degeneration/regeneration

cycles in healthy skeletal muscle and to identify abnormalities in

these processes in pathological conditions as in neuromuscular

diseases. Given some similarities in the histopathological

alterations that follow unaccustomed eccentric actions with

those observed in muscular dystrophy pathology, further

investigations on the eccentric exercise may unravel crucial issues

in molecular mechanisms frequently involved in neuromuscular

diseases. Investigations employing rigorous standardization of

the experimental conditions in the eccentric and other training

groups are necessary to determine the speciﬁc multi-target and to

draw guidelines for eccentric activity prescriptions. In particular,

more eﬀorts should be devoted to develop intensity, duration and

modes of eccentric training optimizing eﬃciency of this method.

AUTHOR CONTRIBUTIONS

SH wrote the manuscript. J-LC, TB, BR, and PL revised the

manuscript according to their respective ﬁeld of expertise.

FUNDING

This work was supported by “Fonds de la Recherche

Scientiﬁque Médicale” grant (FRSM 3.4559.11) from the Belgian

“Fonds de la Recherche Scientiﬁque-Fonds National de la

Recherche Scientiﬁque” (F.R.S.-FNRS). PL is a Senior Research

Associate of F.R.S.-FNRS.

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Conﬂict of Interest Statement: The authors declare that the research was

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be construed as a potential conﬂict of interest.

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Frontiers in Physiology | www.frontiersin.org 18 May 2019 | Volume 10 | Article 536