Uncategorized

March 7, 2018

Reply to the letter to the Editor: “Exercise-Induced Muscle Damage and Hypertrophy: A Closer Look Reveals the Jury is Still Out”

In a recent blog post , I, along with my colleague Bret Contreras, published a “letter to the editor” that raised issue with various claims made in a review of exercise-induced muscle damage. In the spirit of scientific discourse, we invited the authors of the paper – Felipe Damas, Cleiton Libardi, and Carlos Ugrinowitsch – to publish a rebuttal to our letter on my site. They have obliged and what follows is their response.

We acknowledge the authors of the letter to the Editor for the opportunity to continue the debate on the interesting topic of mechanisms related to resistance training (RT)-induced skeletal muscle hypertrophy. While we agree that the role of muscle damage on muscle hypertrophy needs further scientific scrutiny, as we pointed out in our article (Damas et al. 2018a), current evidence indicates that muscle damage promoted by initial resistance exercise (RE) does not predict, explain, or potentiate skeletal muscle hypertrophy induced by weeks of RT (Damas et al. 2016; Flann et al. 2011). Moreover, if muscle damage magnitude is severe, the exercise-induced stress results in maladaptation, segmental necrosis or even muscle atrophy (Butterfield 2010; Eriksson et al. 2006; Foley et al. 1999; Lauritzen et al. 2009). That said, it remains to be elucidated if disturbances within muscle fibres, e.g., Z-band streaming, muscle repair and remodelling are required in early RT phases to prepare muscle tissue to endure further stresses; albeit delayed onset muscle soreness, muscle proteins (e.g., creatine kinase) leakage to bloodstream, or large decreases in muscle function can be avoidable if the goal is muscle hypertrophy (see p.493 of Damas et al. (2018a).

In their letter, the authors mentioned that our original article (Damas et al. 2016) was not designed to test if muscle damage have a role on muscle hypertrophy, what we respectfully disagree. While more intelligent study designs could be drawn to test the hypothesis, we agree with the authors that an investigation that would modulate only the ‘muscle damage’ variable is virtually impossible. However, some points regarding the rational of the research design presented by Schoenfeld and Contreras to test the damage vs hypertrophy paradigm requires further considerations. The comparison between two groups with one demonstrating significant damage in the beginning of RT and another experiencing minimal damage throughout RT has already been performed by Flann et al. (2011) (using muscle soreness and plasma creatine kinase as markers), and they showed similar levels of hypertrophy between groups. Alternatively, maintaining significant damage throughout RT is, as far as we understand, somewhat unfeasible. Firstly because muscle damage is potently attenuated within the first training sessions – repeated bout effect (Barroso et al. 2010; Chen et al. 2009; Clarkson and Hubal 2002; Damas et al. 2016; McHugh 2003), and secondly, to the best of our knowledge, there is no empirical evidence that ‘strategies’ (e.g., changing resistance training variables – volume, intensity, exercises) could overcome the repeated bout effect and further increase or even maintain an initial level of muscle damage. Accordingly, Zourdos et al. (2015) demonstrated that changing elbow flexors exercises between training sessions does not minimize the repeated bout effect. Therefore, in our original article (Damas et al. 2016), we opted to use a reverse logic, maintaining training stimulus as constant as possible, and use the repeated bout effect as strategy to produce distinct muscle damage magnitudes to test the relationship between changes in muscle damage magnitude, myofibrillar protein synthesis (MyoPS) and muscle hypertrophy. Accordingly, we used previously untrained subjects to achieve distinct magnitudes of muscle damage (through direct and indirect muscle damage markers, to form a more complete picture of the process), investigating an early RT phase (i.e., after only 4 RT bouts) as a first ‘attenuated damage’ time-point in which muscle hypertrophy is not significant yet (thus hypertrophic potential is maintained compared to baseline), and relate to acute MyoPS response after the same RT bouts and to muscle hypertrophy induced by 10 weeks of RT. Doing so, we isolated the best way we could the ‘damage’ variable. We also provided the same data for a RT session in the last week of RT. Importantly, our longitudinal design testing the same subjects over time, maintaining exercise mode (isoinertial RT, involving concentric and eccentric phases) with every set to muscle failure (same relative load), allowed significant internal validity while providing ecological validity of our results. We demonstrated that the subjects that had a greater magnitude of muscle damage in the early phase of RT were not the same subjects that showed greater muscle hypertrophy after 10 weeks of RT (correlation analysis). In addition, we showed that MyoPS does not correlate to muscle hypertrophy when damage is the largest (in response to the first RT session), but MyoPS presented a trend to moderately correlate (r ~ 0.6, p = 0.09) to the degree of damage in response to the same RT bout. After progressive attenuation of muscle damage throughout RT, MyoPS strongly correlated (r ~ 0.9) with muscle hypertrophy induced by 10 weeks of RT (but MyoPS showed no association with damage anymore) (Damas et al. 2016). Most likely, the increase in MyoPS at the beginning of RT is directed to repair and remodel muscle tissue and with RT progression and thus damage attenuation, MyoPS increase is focused on muscle hypertrophy. Overall, more (or less) damage, throughout the entire RT program did not correlate at any point with muscle hypertrophy induced by RT. Thus, we suggested, based on our previous work (Damas et al. 2016) and mainly on the discussion developed in our review (Damas et al. 2018a) that muscle damage was not predictive, did not potentiate or explained the magnitude of RT-induced muscle hypertrophy. We are in line with the authors when they argue in their letter that is impossible to determine whether damage is required to occur previously to muscle hypertrophy, repairing and remodelling muscles to be prepared for further stress (Damas et al. 2018a). In fact, in the article the authors cite in their letter (Lilja et al. 2018), the high doses of anti-inflammatory drugs could be interfering in muscle repair and remodelling (involving, for example, enhanced protein turnover, addition of sarcomeres in parallel in response to Z-band streaming). Successful muscle repair and remodelling might be possibly required to endure subsequent RE sessions in the RT program, which in turn, would supress muscle hypertrophy. Indeed, more work is required on this topic.

The authors suggested that we misinterpreted a finding from their previous work (Schoenfeld et al. 2017), as eccentric RT produced an effect size point estimation of 0.25 when compared to concentric RT. In addition, the authors provided the 95% confidence interval of the point estimation of all of the studies included in their meta-analysis. Even though Schoenfeld and Contreras supported their claim based on Hopkins’ magnitude-based inference work, one should consider that confidence intervals, when using a frequentist approach (or credible intervals for a Bayesian approach) are critical to determine the region in which the true population effect value should be included or the actual probability of an event to occur. Nakagawa and Cuthill (2007) provided a good example on the topic:

“The approach of combining point estimation of effect size with CIs provides us with not only information on conventional statistical significance but also information that cannot be obtained from p values. For example, when we have a mean difference of 29 with 95% CI = –1 to 59, the result is not statistically significant (at a level of 0.05) because the CIs include zero, while another mean difference 29 with 95% CI = 9 to 49 is statistically significant because the CI does not include zero.”

This idea is particularly important as the effect size point estimation obtained in a meta-analysis depends on the articles retrieved from the search and may not represent “the true population value”. Thus, effect size confidence interval analysis is imperative as the actual effect size could be any value within the interval. As their confidence interval [-0.03, 0.52] included zero (Schoenfeld et al. 2017), it is possible that the alleged advantage of eccentric RT over concentric RT may be rather smaller or even does not occur. Furthermore, that was not the main point of our argument in the review (Damas et al. 2018a), which was that the evidence indicating superior hypertrophy for eccentric RT is, at least, controversial (please see p.492). The mechanical tension (which should not be confounded as a direct indicator of muscle damage) is greater in a maximal eccentric contraction compared with a maximal concentric contraction, possibly resulting in a greater hypertrophic-induced effect per repetition for the eccentric exercise mode. Indeed, training with the same number of maximal repetitions showed superior hypertrophy for eccentric vs concentric RT (Farthing and Chilibeck 2003). However, when both exercise modes are matched for total work, Moore et al. (2012) showed similar magnitudes of muscle hypertrophy between them. Yet, it needs to be highlighted that different contraction modes seems to rely on distinct mechanisms to induce muscle hypertrophy. For example, it was showed that total work per repetition is greater in eccentric vs concentric RE (Moore et al. 2012; Rahbek et al. 2014), but the voluntary activation of motor units is lower for eccentric RE (Beltman et al. 2004) and metabolic stress is greater following concentric RE (Durand et al. 2003). Therefore, concluding about the role muscle damage to RT-induced muscle hypertrophy using distinct isolated contraction modes, which rely on several mechanisms to promote hypertrophy, may be equivocal. That was imperative for the design choice in our original study (Damas et al. 2016). We maintained exercise mode throughout RT with the same relative load (as explained above), which would rapidly attenuate damage providing different magnitudes of damage to be compared in the same subjects longitudinally. In addition, even with protocols that induce high levels of muscle damage, i.e., maximal eccentric RE, muscle damage is quickly attenuated with RE repetition (Chen et al. 2009) (actually, as curiosity, the greater is initial damage, the stronger is the protective effect (Chen et al. 2007)), questioning the real importance of damage in the long run (i.e., several weeks, months or years of RT). Contributing to this line of argumentation, Rahbek et al. (2014) demonstrated that MyoPS increase post-RE was similar between eccentric and concentric RE after only three RT bouts (i.e., small period of adaptation to RT), despite eccentric RE resulting in greater muscle damage and MyoPS response after a first RT session (Moore et al. 2005).

Finally, we do not claim that satellite cells (SC) are solely involved in muscle regeneration or repair, and not in muscle hypertrophy. We clearly state that “Chronic repetition of RE will maintain SC elevation, replenishing SC niche and enhancing myogenic capacity for future stressful events or muscle fibre hypertrophy” (p.495). However, SC increase early on into RT, as in the scenario in which muscle damage is pronounced, did not result in increased myonuclear number after either isoinertial concentric-eccentric RE (Damas et al. 2018b; Kadi et al. 2004) or a high volume eccentric RE (i.e., 300 repetitions) (Hyldahl et al. 2015). If such an increase in SC resulted in increased myonuclear number due to damage early on into RT, one could suggest increased transcription capacity due to damage, but this was not the case (Damas et al. 2018b; Hyldahl et al. 2015; Kadi et al. 2004). Thus, to this point it is highly speculative to relate the early increase in SC niche, due to stress/damage, to a later on into RT support of muscle hypertrophy, which would undeniably be interesting in low-responders to RT and elderly. Although, one might argue that these populations might not reach a theoretical myonuclear domain threshold that would require an increase in myonuclear number donated by SC (Conceicao et al. 2018; Kadi et al. 2004). SC pool increase in response to unaccustomed stress and muscle damage, and repeated exercise stress seem to keep SC pool elevated, probably as an anticipatory mechanism to aid in possible future stressful events or to support large muscle fibre hypertrophy (to a more in depth discussion see p.493-495). However, there is evidence demonstrating that SC pool was increased in a non-hypertrophic (i.e., aerobic) training (Joanisse et al. 2013), favouring a major role for SC activity related to stress response.

Although we acknowledge that the theme of muscle damage vs hypertrophy requires further testing and elucidations as we mentioned above, it is our understanding that based on current evidence the ball is on the other side of the court, i.e. the hypothesis of damage having a minor (or even large) role in explaining or potentiating muscle hypertrophy is speculative at this point. We look forward to novel study designs testing the damage vs hypertrophy paradigm to continue solidifying evidence-based knowledge on the theme.

References
Barroso R, Roschel H, Ugrinowitsch C, Araujo R, Nosaka K, Tricoli V (2010) Effect of eccentric contraction velocity on muscle damage in repeated bouts of elbow flexor exercise. Appl Physiol Nutr Metab 35:534-540

Beltman JG, Sargeant AJ, van Mechelen W, de Haan A (2004) Voluntary activation level and muscle fiber recruitment of human quadriceps during lengthening contractions. J Appl Physiol 97:619-626

Butterfield TA (2010) Eccentric exercise in vivo: strain-induced muscle damage and adaptation in a stable system. Exerc Sport Sci Rev 38:51-60. doi:10.1097/JES.0b013e3181d496eb
Chen TC, Chen HL, Lin MJ, Wu CJ, Nosaka K (2009) Muscle damage responses of the elbow flexors to four maximal eccentric exercise bouts performed every 4 weeks. Eur J Appl Physiol 106:267-275. doi:10.1007/s00421-009-1016-7

Chen TC, Nosaka K, Sacco P (2007) Intensity of eccentric exercise, shift of optimum angle, and the magnitude of repeated-bout effect. J Appl Physiol (1985) 102:992-999

Clarkson PM, Hubal MJ (2002) Exercise-induced muscle damage in humans. Am J Phys Med Rehabil 81:S52-69. doi:10.1097/01.PHM.0000029772.45258.43
Conceicao M et al. (2018) Muscle fibre hypertrophy to myonuclei addition:A systematic review and meta-analysis. Med Sci Sports Exerc in press

Damas F, Libardi CA, Ugrinowitsch C (2018a) The development of skeletal muscle hypertrophy through resistance training: the role of muscle damage and muscle protein synthesis. Eur J Appl Physiol 118:485-500. doi:10.1007/s00421-017-3792-9

Damas F et al. (2018b) Early- and later-phases satellite cell responses and myonuclear content with resistance training in young men. PLoS One 13:e0191039. doi:10.1371/journal.pone.0191039

Damas F et al. (2016) Resistance training-induced changes in integrated myofibrillar protein synthesis are related to hypertrophy only after attenuation of muscle damage. J Physiol 594:5209-5222. doi:10.1113/JP272472

Durand RJ et al. (2003) Hormonal responses from concentric and eccentric muscle contractions. Med Sci Sports Exerc 35:937-943

Eriksson A, Lindstrom M, Carlsson L, Thornell LE (2006) Hypertrophic muscle fibers with fissures in power-lifters; fiber splitting or defect regeneration? Histochem Cell Biol 126:409-417. doi:10.1007/s00418-006-0176-3

Farthing JP, Chilibeck PD (2003) The effects of eccentric and concentric training at different velocities on muscle hypertrophy. Eur J Appl Physiol 89:578-586. doi:10.1007/s00421-003-0842-2

Flann KL, LaStayo PC, McClain DA, Hazel M, Lindstedt SL (2011) Muscle damage and muscle remodeling: no pain, no gain? J Exp Biol 214:674-679. doi:10.1242/jeb.050112
Foley JM, Jayaraman RC, Prior BM, Pivarnik JM, Meyer RA (1999) MR measurements of muscle damage and adaptation after eccentric exercise. J Appl Physiol (1985) 87:2311-2318

Hyldahl RD et al. (2015) Extracellular matrix remodeling and its contribution to protective adaptation following lengthening contractions in human muscle. FASEB J 29:2894-2904. doi:10.1096/fj.14-266668

Joanisse S, Gillen JB, Bellamy LM, McKay BR, Tarnopolsky MA, Gibala MJ, Parise G (2013) Evidence for the contribution of muscle stem cells to nonhypertrophic skeletal muscle remodeling in humans. FASEB J. doi:fj.13-229799 [pii]
10.1096/fj.13-229799

Kadi F, Schjerling P, Andersen LL, Charifi N, Madsen JL, Christensen LR, Andersen JL (2004) The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles. J Physiol 558:1005-1012. doi:10.1113/jphysiol.2004.065904

Lauritzen F, Paulsen G, Raastad T, Bergersen LH, Owe SG (2009) Gross ultrastructural changes and necrotic fiber segments in elbow flexor muscles after maximal voluntary eccentric action in humans. J Appl Physiol (1985) 107:1923-1934. doi:10.1152/japplphysiol.00148.2009

Lilja M et al. (2018) High doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults. Acta Physiol (Oxf) 222. doi:10.1111/apha.12948

McHugh MP (2003) Recent advances in the understanding of the repeated bout effect: the protective effect against muscle damage from a single bout of eccentric exercise. Scand J Med Sci Sports 13:88-97

Moore DR, Phillips SM, Babraj JA, Smith K, Rennie MJ (2005) Myofibrillar and collagen protein synthesis in human skeletal muscle in young men after maximal shortening and lengthening contractions. Am J Physiol Endocrinol Metab 288:E1153-1159. doi:10.1152/ajpendo.00387.2004

Moore DR, Young M, Phillips SM (2012) Similar increases in muscle size and strength in young men after training with maximal shortening or lengthening contractions when matched for total work. Eur J Appl Physiol 112:1587-1592. doi:10.1007/s00421-011-2078-x

Nakagawa S, Cuthill IC (2007) Effect size, confidence interval and statistical significance: a practical guide for biologists. Biol Rev Camb Philos Soc 82:591-605. doi:BRV27 [pii]
10.1111/j.1469-185X.2007.00027.x

Rahbek SK, Farup J, Moller AB, Vendelbo MH, Holm L, Jessen N, Vissing K (2014) Effects of divergent resistance exercise contraction mode and dietary supplementation type on anabolic signalling, muscle protein synthesis and muscle hypertrophy. Amino Acids 46:2377-2392. doi:10.1007/s00726-014-1792-1

Schoenfeld BJ, Ogborn DI, Vigotsky AD, Franchi MV, Krieger JW (2017) Hypertrophic Effects of Concentric vs. Eccentric Muscle Actions: A Systematic Review and Meta-analysis. J Strength Cond Res 31:2599-2608. doi:10.1519/JSC.0000000000001983

Zourdos MC et al. (2015) Repeated Bout Effect in Muscle-Specific Exercise Variations. J Strength Cond Res 29:2270-2276. doi:10.1519/JSC.0000000000000856