Eccentric Exercise as a Potent Prescription for Muscle Weakness After Joint Injury

Abstract

Lengthening contractions (i.e., eccentric contractions) are capable of uniquely triggering the nervous system and signaling pathways to promote tissue health/growth. This mode of exercise may be particularly potent for patients suffering from muscle weakness after joint injury. Here we provide a novel framework for eccentric exercise as a safe, effective mode of exercise prescription for muscle recovery.

INTRODUCTION

Muscle weakness after joint injury is known to be secondary to a complex manifestation of neurological and morphological events that directly interfere with the system’s ability to communicate and regulate the health of muscle (1). Despite this knowledge base and clinician’s best efforts, many current rehabilitative efforts fall short in effectively treating muscle weakness (2, 3). This common outcome is concerning as insufficient strength recovery (i.e., diminished muscle force generating capacity) is prospectively associated with an elevated re-injury risk, early joint degeneration, life-long reduced physical activity levels and diminished quality of life (4). Improving muscle strength stands to have far-reaching positive effects, yet a rehabilitation regime that effectively treats the neurological and morphological origins of muscle weakness after joint injury has yet to be identified.

Joint injury is known to cause an immediate shut-down of neural signaling that is required to activate the muscle (5). This disruption in neural activity compromises muscle tissue volume and quality as a result of the system’s decreased ability to effectively discharge action potentials that are necessary for maintaining muscle homeostasis. Importantly, modes of exercise that therefore rely on the patient to use their neural drive to control the contraction (6–8) have been rendered ineffective as full, sustained muscle contractions after joint injury are not possible.

Lengthening contractions (i.e., eccentric contractions) are an attractive alternative to muscle shortening contractions, as they are capable of uniquely triggering the nervous system and signaling pathways that promote tissue health/growth (9, 10). We and others have shown the promise of an eccentrically biased mode of exercise prescription to positively promote muscle recovery after joint injury (11–13). These findings have been documented using electromyographical, neuroimaging, immunoblotting, and immunostaining techniques, offering several layers of new insight into the beneficial adaptations of eccentric exercise. Though the basis for this exercise prescription is gaining traction, eccentric contractions have long been associated with muscle injury (14), thus there is still a reluctance in the clinical community to adopt it. This review provides evidence supporting the hypothesis that the incorporation of lengthening exercises into musculoskeletal rehabilitation can be a safe, effective mode of exercise prescription to promote muscle recovery. We believe these adaptations are largely regulated by improvements in neural drive and cellular signaling that are responsive to stretch and the repetitive lengthening of an activated muscle.

MULTITUDE OF FACTORS THAT IMPEDE MUSCLE RECOVERY AFTER JOINT INJURY

As reviewed in other articles (5, 15), joint trauma initiates a series of events that interfere with the nervous systems’ ability to communicate with the muscle. Briefly joint injuries (e.g., ligament tears and sprains) are known to cause short-term alterations in afferent neural activity because of pain and swelling, and the loss of mechanoreceptors in the injured joint. Reflexive neural adaptations are also present and serve to further depress the volitional activation of the supporting musculature, increasing demand on the central nervous system to generate muscular force. These deficits are also compounded by alterations in descending pathways that reduce the transmission of motor impulses to the alpha-motoneurons that innervate the muscle. At the cellular level the absence of typical neural activity disrupts post-synaptic homeostasis which triggers a decline in muscle tissue quality (i.e., the tissue becomes more fibrotic) (16). This disruption in neural activity is associated with widespread muscle volume loss (i.e., atrophy) and weakness (Figure 1) (3). Though the initial atrophic response of muscle appears to be driven by neural influences, with time, atrophy is the result of multiple contributing mechanisms. To this point, there are several other key regulators of muscle growth/health that are also known to be compromised after joint injury, and these include an abundance of pro-inflammatory cytokines, reduced number of satellite cells, increased fibrogenic alterations and a shift from cellular proteostasis to an imbalance that favors protein degradation (1). In order to effectively treat muscle weakness after joint injury, clinician must prescribe therapeutic interventions capable of targeting the neurophysiological origins.

Figure 1.

Model summarizing the events in healthy muscle and in muscle after traumatic joint injury. Left side: Action potential (AP) propagation down the alpha-motor neuron (alpha-MN) results in post-synaptic depolarization, calcium (Ca²⁺) release, and cross-bridge cycling. The creation of mechanical tension during contraction activates/maintains pathways of muscle homeostasis. Right side: After injury, the lack of AP propagation interferes with calcium (Ca²⁺) balance, inhibiting the removal of tropomyosin from myosin binding sites and other regulatory processes that interferes with cross-bridge cycling. This leads to contractile dysfunction and disrupts the homeostatic balance necessary for the maintenance of muscle tissue quality & quantity.

MISAPPLICATION OF BENCHTOP MODELS TO THE CLINIC

Scientists have long used lengthening contractions as a model to deeply study muscle injury (i.e., the loss of muscle function with evidence of physical disruption). Classically this has been accomplished using in-situ stretch protocols, where researchers have anesthetized rodents and surgically removed the distal point of a long tendon from the bone so that tendon could then be attached to a servo motor or linear actuator (17). The advantage of this setup is that it linearizes the muscle-tendon unit and permits easier measurement of its length and the imposed stretch during contraction. Fundamentally, these in-situ experiments have shown that when a muscle is stretched beyond optimal length, significant injury occurs. This finding of sarcomere rupture with stretch has also been reported at the 1) single muscle fiber-level, 2) via mathematical models (18), and 3) in animals and humans exposed to prolonged bouts of eccentric exercise (19, 20). Although these experiments have undoubtedly added to our understanding of muscle injury, these concepts have been misapplied to the clinic. Thus, it is critically important not to directly translate the findings of bench experiments for the following reasons: 1) the ability for muscle and the elastic properties of the tendon to resist fiber injury is compromised in the in-situ experiments as the tendon has been surgically removed from the bone; 2) single muscle fiber experiments use ‘skinned’ muscle fibers, meaning that all of the protective outer connective tissue elements are removed via chemical or mechanical means; 3) the original mathematical models of sarcomere instability fail to include titin (18); newer updated models that include this giant biological spring do not come to the same conclusion (21); 4) the use of prolonged bouts of eccentric exercise in untrained animal models and humans have been done so to induce muscle damage. In animals this often amounts to rodents running >90 mins on a treadmill at a 16 degree negative slant, commonly leading to the loss of toenails (19, 20). In humans, this has meant that untrained participants often perform anywhere between 100–300 repetitions at maximal or supramaximal loads (22). To summarize, the anatomical adjustments made to the muscle-tendon unit in these experimental models or the notion that rehabilitation specialists would recommend that untrained humans would train to significant injury simply does not translate well to the clinic. With care, the use of concentrated lengthening contractions during rehabilitation has decided advantages.

EFFECT OF CLINICALLY TRANSLATIONAL DOSES OF ECCENTRIC EXERCISE

To address some of these issues, we have tested the direct effect of an initial bout of eccentric exercise on muscle in an untrained animal model (23). The goal of this experiment was to determine if a single bout of eccentric exercise causes muscle damage under normal physiological conditions when the anatomy is not adjusted and the animal is simply walking at a clinically translational dose (i.e., 15 mins of exercise in total, 5 min bouts, 2 mins of rest between bouts). Relative to an equal dose of concentric exercise and control/non-exercised rats, we show that there is very limited evidence of muscle damage in our experiments that utilized in-tact muscle-tendon units (Figure 2). To this point, greater than 9000 vastus lateralis muscle fibers (in 40 animals) were examined for muscle damage via positive immunoglobulin G infiltration and only one fiber was found to have signs of membrane rupture, and this happened to come from the concentric group. We also showed that a single bout of eccentric exercise was superior to concentric exercise for triggering pathways responsible for muscle growth, as a 20-fold increase in the protein synthesis rate was found in the eccentrically exercised animals compared to the concentric group, which likely represents an initial step towards adaptive sarcomere remodeling (17). These data reinforce other key observations that our group has made in animals exposed to chronic forms of eccentric exercise (24). Briefly in the same animal model, we have also shown that 10 days of eccentrically biased treadmill running (downhill running for a range of 15–35 mins) results in muscle growth as a significant addition of serial sarcomeres was identified in some muscles, whereas the concentrically biased exercise group (uphill treadmill training) was found to have lost serial sarcomeres. This finding of differential sarcomere growth response to eccentric (i.e., increase in serial sarcomeres) and concentric (i.e., decrease in serial sarcomeres) exercises has also been reported by others (25) and is theorized to be part of the repeated bout effect that makes muscles less susceptible to eccentric induce stress from a prior exposure (26). Others have suggested that the delayed onset muscle soreness that is common after the first bout may be a pro-inflammatory response that is largely attenuated with repeated exposures (27).

Figure 2.

Effect of exercise contraction type on muscle-fiber damage. Representative images of immunoglobulin G (IgG) staining (green) of the vastus lateralis in eccentric (A & B) and concentric (C & D) exercise groups euthanized at 6 (A & C) and 24-hours post-exercise (B & D). 2C. The yellow circle surrounds a damaged fiber, indicated by the lesions in the sarcolemma and subsequent IgG infiltration into the muscle fiber (Reprinted from Lepley LK. Morphology and Anabolic Response of Skeletal Muscles Subjected to Eccentrically or Concentrically Biased Exercise. J Athl Train. 2020 Apr;55(4):336-342. Copyright © 2020 National Athletic Trainers' Association. Used with permission.)

Without detailed methodological knowledge, it is understandable why the results from many experiments would sway clinicians away from eccentric exercise. However, we argue that it is time for clinicians to fundamentally re-evaluate their classic beliefs about lengthening contractions as our experiments that use in-tact muscle-tendon units and translational doses of exercise directly show that lengthening exercises are not necessarily damaging but rather a potent stimulus for muscle growth.

RE-EVALUATING CLASSIC BELIEFS ABOUT THE SAFETY OF ECCENTRIC EXERCISE

Concentric and isometric contractions are well described by the molecular theories of muscle contraction that were first explained in the 1950s by Huxley and Niedergerke (28), and Huxley and Hanson (29), however the mechanisms of eccentric contractions are not. In fact, the term ‘eccentric’ means unconventional or odd and this descriptor was given to lengthening contractions as scientists simply did not understand how they work. More recently, work led by Herzog in 2014 (21) has begun to help explain some of the phenomenon observed during muscle lengthening at the sarcomere-level. By adapting A.V. Hill’s 1938 (30) structural two-element model (later defined as actin and myosin) to a three-element model (actin, myosin, and titin) scientist now show that lengthening contractions enhance force production and do not necessarily lead to significant fiber injury thanks to the giant elastic protein titin that spans the length of the sarcomere and is responsible for contributing active/passive tension and the stability of sarcomeres during lengthening actions. Thus, we now have mathematical models and experimental data that can explain how eccentric contractions work at the sarcomere-level and show that they can be used safely. Clinical data is also available that shows the promise of an eccentrically biased mode of exercise prescription to positively promote muscle recovery after joint injury (i.e., the re-establishment of muscle strength and size )(11–13). Accordingly, the following sections support the hypothesis that the incorporation of lengthening contractions into musculoskeletal rehabilitation is an effective mode of exercise prescription to treat neural and morphological deficits. We believe these adaptations are largely regulated by improvements in neural drive and cellular signaling that are responsive to stretch and the repetitive lengthening of an activated muscle. The sections below detail this working theory (see, Figure 3 for theoretical model).

Figure 3.

Theoretical model summarizing the ability of lengthening contractions (eccentric exercise) to attend to the multitude of factors after joint injury that work to degrade muscle tissue health and volume. Left side: Eccentric contractions may positively influence neural recruitment by counteracting the afferent/reflexive inhibitory signals that arise from the injured joint as this mode of exercise is principally controlled by supraspinal factors. Right side: The higher mechanical stress produced during eccentric actions activates titin and other mechanoresponsive pathways that promote hypertrophic gene expression and protein quality control, resulting in improved tissue quantity and quality. Bottom: The consequent increases in muscle activation and muscle hypertrophy translate to reduced reinjury risk, improved muscle strength, and increased functional outcomes.

POSITIVE ADAPTATIONS TO NEURAL DRIVE

As stated above, joint injury is known to cause an immediate loss of neural signaling that is required to volitionally activate the muscle (15). In the acute stage, alterations in reflexive excitability interfere with the modulation of monosynaptic activity and/or Ia input from the muscle spindle. Adaptations in type Ib, II, III, and IV input are also commonly reported and serve to further derail the necessary afferent input required for muscle strength recovery. These widespread alterations may help to explain why multiple systematic reviews have found concentrically biased rehabilitation programs to be unsuccessful (2, 3), as concentric exercises predominantly rely on inhibited afferent and reflexive pathways to produce full sustained muscle contractions (6, 7). An alternative form of exercise prescription that can effectively bypass or treat the inhibited pathways may be key to promoting muscle recovery after joint injury.

There is overwhelming evidence that training with eccentric exercise leads to potent strength gains. At the peripheral level, scientists have long shown that exercising with lengthening contractions is associated with less neuromuscular activity at the sarcolemma, due in part to the reliance on passive structures for force production, and also due to neural influences. At the neural-level, some have postulated that these reductions in muscle action potential activity occur via modulations in afferent and reflexive pathways in order to protect the muscle against damage. This idea is centered around the tension-limiting hypothesis that suggests that inhibitory feedback from sensory receptors (primarily via golgi tendon organs or Ia afferents) during eccentric contractions depresses the responsiveness of the alpha-motoneuron pool to incoming inputs. Importantly, when scientists have directly tested this theory, they find the tension-limiting hypothesis does not hold up as the amplitude of electromyographic activity that should dampen as the intensity of eccentric actions rises remains unchanged (31). Building on this observation, others have also shown that a depression in electromyographic amplitude is already present during a maximal isometric contraction that precedes an eccentric contraction (32). This depression in electromyographic amplitude has been attributed to an earlier onset of supraspinal activation that is engaged in order to plan for more movement complexity. Altogether these studies (31, 32) and others point to the idea that eccentric contractions are not dependent on afferent and reflexive pathways but are principally controlled by supraspinal factors.

Using techniques that measure the responsiveness of the corticospinal tract, researchers have indeed found that supraspinal factors are uniquely activated with muscle lengthening contractions (33). Specifically, short interval intracortical inhibition has been found to be reduced while intracortical facilitation is increased. These observations suggest that compared with concentric contractions, eccentric contractions enhance cortical excitability possibly via a unique stretch-related transcortical reflex that is activated to control a lengthened muscle (34). Others have also shown that training with eccentric exercise leads to beneficial adaptations at the spinal level, as an eccentrically induced increase in cortical excitability has been found to cause a net decrease in presynaptic inhibition (33). This decrease in presynaptic inhibition could help to improve neural recruitment and potentially counteract the inhibitory signals that arise from the injured joint. To this point, we have found that training with eccentrics contractions improves the magnitude and firing rate of alpha-motoneurons, resulting in greater strength recovery and knee movement profiles in those with a significant history of joint injury (e.g., anterior cruciate ligament injury) relative to concentrically treated patients (13). These data indicate that eccentric exercise can produce improvements in neural drive that translate to functional improvements for the patient.

Neuroimaging studies offer yet another layer of evidence into the beneficial adaptations of eccentric exercise to the nervous system. Fundamentally, it has been established that to accomplish a task, an individual with a history of joint injury upregulates areas of the brain responsible for planning, motor control, and visual input. Our data show that eccentric contractions are capable of uniquely targeting this maladaptive brain activation strategy (35, 36). Specifically, we show that exercising with lengthening contractions after anterior cruciate ligament injury promotes heighted feed-forward control (via the cerebellum) that helps to regulate motor output and reduce motor coordination error (35). We further demonstrate that exercising the opposite/non-injured limb with eccentric contractions (therapy known as cross-exercise or cross-education) promotes a more neurally efficient environment, as there is reduced dependence on the frontal cortex to generate muscle contractions in the injured limb (36). We also show signs of enhanced spinal-reflexive and descending neural excitability in response to eccentric exercise during a time in recovery when these pathways are known to be depressed (36). Altogether, these observations directly support our overarching premise that eccentric exercise is good for neural drive after injury.

The trouble with relying on concentric exercises after joint injury, is that this mode of exercise predominantly relies on inhibited afferent and reflexive pathways to produce muscle contractions (6, 7). Because of this, concentrically bias rehabilitation programs often fail to adequately restore muscle strength despite ≥6 months of therapy (2, 3). The extensive unilateral concentric muscle strengthening utilized during rehabilitation may also contribute to the heightened use of conscious cortical mechanisms to maintain joint stability during activity (35). By incorporating lengthening contractions in rehabilitation protocols, clinicians may also be able to reduce primary and secondary injury risk by selectively targeting the cerebellum, which should free up higher-order resources for task complexity, while reducing motor coordination error.

The ability to effectively bypass or treat the pathways of inhibition after joint injury is integral to recovery. Our data and others collectively point to the power of lengthening contractions to induce positive neural adaptations that ultimately could enhance muscle strength recovery. Because of its proven ability to address the injury-induced neuroplasticity that leads to strength loss, we strongly encourage clinicians to reconsider this mode of exercise to treat neurogenically mediated strength loss after joint injury.

STRUCTURAL AND ANABOLIC RESPONSES

Muscle atrophy is difficult to treat after traumatic joint injury as it is attributed to a unique profile that is acutely driven by neurogenic mechanisms and chronically associated with key imbalances in factors integral to muscle health (e.g., abundant pro-inflammatory cytokines, reduced satellite cells, and the accumulation of fibrotic tissue) (16, 37). To break the sequelae, countermeasures require a therapeutic prescription that is capable of targeting these components or triggering the system to promote muscle hypertrophy despite the multitude of factors that are present and work to degrade muscle tissue health and volume.

Progressive overload via mechanical tension is widely regarded as a primary mediator of muscle hypertrophy as it promotes increased protein translation and the upregulation of genes involved in anabolic signaling (9). Although concentric exercise can harness this mechanism, the higher mechanical stress produced during muscle lengthening contractions is a potent stimulus for muscle hypertrophy (9) as it is able to more effectively engage key stretch-sensing molecules at the sarcomere-level. Observations of this increased tension during active muscle lengthening date back to Fick’s experiments in 1882 (38) and have been further expanded up by Huxley & Niedergerke 1954 (28), Nishikawa et al., 2012 (39), and Herzog 2014 (21). Researchers have shown that the giant elastic protein titin that spans the entire length of a sarcomere is responsible for a significant portion of the tension during lengthening. Titin, a filamentous protein made up of immunoglobulin-like domains, fibronectin-type-3, and unique sequences that spans from the M-band to the Z-line, acts as a molecular spring unfolding during contraction to increase sarcomere stiffness. In addition, recent findings also indicate that the increased tension during lengthening is attributed, in part, to neural adaptations. As the nervous system employs a different recruitment strategy during lengthening contractions (e.g., decreased number of recruited motor units and unit discharge) there is a higher level of tension per motor unit relative to concentric and isometric contractions. This increased tension/stretch during lengthening contractions via contractile and neural components provides a potent mechanical stimulus for activating mechanoresponsive pathways.

The ability to convert mechanical stress to a molecular signal is largely attributed to the activation of mitogen-activated protein kinases (MAPKs). MAPKs are a family of proteins that respond to external stresses and translate those signals to intracellular responses that lead to growth and differentiation. Though exercise is known to generally active MAPKs, it is clear that the mode and dose of exercise prescription matter. In particular, MAPKs such as c-Jun N-terminal kinase and extracellular regulated kinase, are known to be responsive to mechanical stress in a dose-dependent manner, with eccentric contractions inducing the greatest MAPK phosphorylation rates relative to isometric and concentric exercises (31). This anabolic response is highly beneficial, as activation of this signaling cascade is known to result in myogenic differentiate, a precursor to muscle growth (40). Other key pathways that can be activated by stretch such as the Akt/mammalian target of rapamycin (mTOR) pathway have also been reported to be upregulated after eccentric exercise (41). For instance, in our own work, a 20-fold increase in the ribosomal protein S6 kinase (an essential hypertrophic protein) (42) was found in the eccentrically exercised animals compared to the concentric after just a single 15-min dose (23).

The giant elastic protein, titin, has also been shown to play a uniquely important role for inducing hypertrophic responses during eccentric exercise (10, 43, 44). Specifically, when a sarcomere is elongated by mechanical stretch, titin unfolds at the I-band, which mechanically opens an adenosine triphosphate binding site at the sarcomeric M-band that directly triggers the phosphorylation of the titin-kinase domain. Activation of the titin-kinase is important, as this domain acts as a biological sensor that initiates the activation of multiple pathways that control hypertrophic gene expression. Notably, only a positive stretch of the sarcomere allows phosphorylation of titin-kinase that begins a cascade of signaling events that ultimately promote exercise-specific tissue growth. The positive mechanical stress achieved through progressive overloading in conjunction with sarcomere strain appears to be a critical component in efficiently promoting beneficial muscle adaptations. Notably, the mechanical engagement of titin is not only linked to hypertrophic signaling, but it is also linked to protein quality control (6), as the activation of titin during eccentric actions has been shown to mediate the degradation of many cytoskeletal elements (i.e., troponin, nebulin, telethonin) that promote sarcomere stability.

Other factors known to trigger hypertrophic signaling could also play an amplifier role when mechanical tension reaches a certain threshold during eccentric exercise. In our scenario, muscle remodeling during higher intensities of eccentric contractions may be due to the rise in the titin-based monofilament stiffness during active lengthening contractions (achieved via calcium binding in the PEVK region of titin) that may serve to further amplify the stretch-related growth mechanisms (39). Further, though overt muscle damage is unlikely at clinically translational doses, the potential role of lengthening contractions to promote hypertrophy may be due to the higher levels of both mechanical tension and microtrauma that could occur during lengthening contractions (45). The advantage of this, is that repetitive minor damage is known to lead to more efficient protein turnover with less degradation and more protein synthesis (26). The higher levels of tension could also induce mechanochemical signals that trigger the activation of satellite cells, which fundamentally would serve to grow/remodel new tissue (46). To this point, evidence of enhanced satellite cell activation has been well established in response to a bout of eccentric exercise.

It is worth noting that eccentric contractions also change the structure and function of the muscle’s extracellular matrix (ECM) and tendon (11). Generally, the tendon will remodel to handle greater loads from the hypertrophied muscle by increasing its cross-sectional area. This will enable the tendon to store elastic energy in a more efficient manner decreasing the likelihood of musculotendinous injury while enhancing force production. Exercising with lengthening contractions is also accompanied by the positive remodeling of the ECM, which may help to counteract the infiltration of fibrotic tissue that is known to occur after traumatic joint injury (16).

Altogether, the complexity of muscle atrophy after traumatic joint injury requires a therapeutic approach that is capable of triggering the system to promote muscle growth despite the multitude of factors that are present and work to degrade muscle tissue health and volume. Progressive overload via mechanical tension is a powerful mediator of hypertrophy, and the combined effects of active and passive stretch with eccentric exercise create for a more potent activation of mechanoresponsive pathways. Given the chronic issues that plague many with a history of traumatic joint injury, exercising with lengthening contractions appears to be an effective rehabilitation strategy towards combating muscle atrophy.

CONCLUSIONS

Though the basis for an eccentric exercise prescription is gaining traction, eccentric contractions have long been associated with muscle injury. Thus, there is still a reluctance in the clinical community to adopt it. With this review, we aim to stimulate dialog and reflection about current practice patterns and the ability of eccentric contractions to safely improve muscle recovery after traumatic joint injury. We encourage clinicians to responsibly consider the use of isolated lengthening exercises to attend to the multitude of factors after joint injury that work to degrade muscle tissue health and volume. We point therapists to a series of original clinical articles that provide protocols that can be used as a guideline for development, that have proven gains, that may be especially useful during the initiation phase when soreness is common (47–49). We also caution that eccentric exercise is a potent stimulus and that excessive overtraining with these contractions does pose a risk. The notion that ‘more is better’ does not apply to exercising with lengthening contractions, as overtrained animals/humans trigger catabolic pathways and a decrease in performance (50).

SUMMARY for table of contents:

An argument for the incorporation of lengthening contractions during rehabilitation after joint injury.

KEY POINTS:

• -Lengthening contractions (i.e., eccentric contractions) are capable of uniquely triggering the nervous system and signaling pathways to promote tissue health/growth.

• -This mode of exercise may be particularly potent for patients suffering from muscle weakness after joint injury.

• -Here we provide a novel framework for eccentric exercise as a safe, effective mode of exercise prescription for muscle recovery.