Hypertrophy mechanisms [2/3] - Muscle Damage [Part 1/2]

Each muscle fiber is a single, multinucleated cell, made up of smaller units called myofibrils. Myofibrils have a repeating pattern called a sarcomere, which is the basic functional unit of muscles. The myofibril is made up of even smaller structures called myofilaments, which are long chains of proteins actin and myosin

Another set of proteins regulates the interaction between actin and myosin. In the actin thin filament there’s a binding site that a myosin head can reach and grab, but the binding sites are covered. Calcium causes configurational changes and uncovers the binding sites for myosin. This calcium is stored in muscle cells in the sarcoplasmic reticulum distributed around the myofibrils.

Strength training can result in localized muscle tissue damage. When a certain threshold is exceeded, sarcomeres break. (It is assumed that optimum sarcomere length is 2.5 μm). This damages contractile elements or myofibrillar structures, disrupts the sarcolemma and sarcoplasmic reticular, causes damage to supportive connective tissue and injuries in the cytoskeleton (1). 

This damage generate a hypertrophic response (2, 3). Muscle damage is a frequent response after unaccustomed exercise, or when performing high intensity exercise. A trainee may experience stiffness and delayed-onset muscle soreness. Other metabolic consequences are increases in creatine-kinase, muscle troponin I, myoglobin and heavy myosin chain (4).

Eccentric actions

The best way to induce micro tears is by emphasizing eccentric training. The eccentric contraction has been proven through countless studies to cause the most damage, which has been shown to mediate a hypertrophic response (5,6), causing myofibrillar remodeling (7,8).

The distribution of sarcomeres on each myofibril is nonuniform, the weakest sarcomeres are located at different regions. This nonuniform lengthening causes a shearing of myofibrils and deforms membranes (4).

The presence of disrupted sarcomeres in myofibrils and damage to the excitation–contraction (E–C) coupling system are signs of damage in a muscle from eccentric exercise (9).

During active stretch of a muscle, most of the length change will be taken up by the weakest sarcomeres (10) in myofibrils (the weakest half-sarcomeres). These sarcomeres become progressively weaker and then lengthen rapidly, uncontrollably, to a point of no myofilament overlap. Then overstretched sarcomeres are distributed at random along muscle fibers. When the muscle relaxes, some myofilaments in the majority of overstretched sarcomeres become disrupted (11).

During repeated eccentric contractions it is postulated that the number of disrupted sarcomeres grows, until a point is reached where membrane damage occurs. It is at this point that damage to elements of the E–C coupling machinery becomes apparent. Subsequently the fiber may die (12) (Fig. 1).

Membrane damage begins with tearing of t-tubules followed by damage to the sarcoplasmic reticulum, uncontrolled Ca2+ release. If the damage is extensive enough, parts of the fiber, or the whole fiber may die. Breakdown products of dead and dying cells would lead to a local inflammatory response associated with tissue oedema and soreness (12). Although it’s not clear, the first step in the damage process can be t-tubule rupture, leading to inactivation of some sarcomeres, but the reverse sequence beginning with sarcomere disruptions can also lead to t-tubule damage (12).

There are also observations of abnormal t-tubular arrangements after eccentric exercise (13).

Eccentric actions and force generation

Muscles achieve higher absolute forces when contracting eccentrically (14,15,16). Heavy negatives, or supramaximal eccentric actions involve eccentric contractions at a weight greater than concentric 1RM. It has been shown that eccentric strength is approximately 20–50% greater than the concentric strength (17) and even predicted to be up to 64% greater (52).

Eccentric contractions could stimulate greater adaptations (18), because increases in strength are thought to be proportional to the magnitude of force developed (19). 

Eccentric training is more effective at increasing total and eccentric strength than concentric training, and appears to be more effective at increasing muscle mass than concentric training, possibly because of the higher forces developed. Adaptations after eccentric training are highly specific to the velocity and type of contraction (20).

Eccentric exercise preferentially recruit fast twitch muscle fibers (53,21,22,23) and perhaps recruitment of previously inactive MUs (21,24). This results in an increased mechanical tension in type II fibers, which have the greatest potential for muscle growth (53,25,26,27).

Compared with concentric contractions, eccentric contractions also produce less fatigue and are more efficient at metabolic level. Unaccustomed eccentric contractions produce transient muscle damage, soreness and force impairments.

Eccentric actions and protein synthesis

Passive muscular tension develops because of lengthening of extra myofibrillar elements, especially collagen (28). This increases the active tension enhancing the hypertrophic response.

Eccentric contractions elicits greater gains in lean muscle compared with concentric and isometric contractions (29,30,31,32). Maximal muscle hypertrophy can only be attained if eccentric muscle actions are performed (33).

When lifting the same weight concentrically and eccentrically no significant difference between the two contractions is observed, if volume is equalized. However in a few studies there’s was a slight advantage for the excentric actions (34,54). Excentric actions are best done supramaximal, above 1RM concentric load.

Lengthening the muscle increase protein synthesis more than a concentric contraction (34), in part by releasing phosphatidic acid, which encourages protein synthesis (35). Another pathway is through the activation of satellite cells located on the outside of muscles. Satellite cells move to the damaged area and fuse to muscle, becoming a part of it (36), increasing muscle fiber size by the addition of the satellite cell's nucleus to the muscle.

The more nuclei, the greater the growth potential. Plateau happens when we can't adequately activate satellite cells (37,38), therefore maximize eccentric loading may be very beneficial.

Other increases have also been observed, such as a faster rise in protein synthesis (39), greater increases in IGF-1 messenger RNA (mRNA) expression (40), and more pronounced elevations in p70S6k (41), when compared with other types of contractions.

As for the tempo, faster speed eccentric contractions release more growth factors, more satellite cells, and greater protein synthesis than slow speed eccentric contractions (42,43). A 2- to 3-second tempo is hypothesized to be ideal for maximizing a hypertrophic response (43).

Eccentric training is also associated with an increased metabolic stress. Higher eccentric intensities elevate lactate buildup and spike anabolic hormonal levels (44).

However another important note: acute measures (1-6h post exercise) of MPS following an initial exposure to RE in novices are not correlated with muscle hypertrophy following chronic RT (55). There’ also a review on the relationship between acute of muscle protein synthesis response and changes in muscle mass (56). Muscle protein breakdown is also important for the regulation of muscle hypertrophy on the long term, and the chronic (positive) balance between MPS and MPB is more important.

Muscle swelling and soreness

In human subjects, the initial fall in tension after eccentric exercise is followed by a slow rise over 2–4 h, presumably recovery from metabolic exhaustion. Then 24 h later there’s a second fall in tension (45).

Eccentric exercise is followed by sensations of stiffness and soreness the next day (46), transient muscle damage, soreness and force impairments (47).

Because of eccentric exercise the contracting muscle is forcibly lengthened. Delayed muscle soreness sets in at about 6–8h after the exercise and peaks at about 48 h (45,48). A second bout of eccentric exercise, a week after the first, leaves us much less stiff and sore.

The injury triggers a local inflammatory response that is accompanied by some oedema. The breakdown products of injured tissues sensitize nociceptors (12,45,49). These nociceptors respond to stimuli that are normally non-noxious, leaving the muscle tender to local palpation, stretch and contraction. A component of the delayed soreness from eccentric exercise may involves large-fiber mechanoreceptors (50,51).

The repair mechanism involves the addition of sarcomeres to regenerating muscle fiber, as shown by animal experiments.

Neutrophils migrate to the area of micro trauma. Damaged fibers release several agents that attract macrophages and lymphocytes to the injury site. The purpose of macrophages is to remove cellular debris and to produce cytokines that activate myoblasts, macrophages and lymphocytes. This response triggers the release of various growth factors that regulate satellite cell proliferation and differentiation (44).

Would you like to know more? Subscribe!

Read Part 2:

Also read:


1. Hill, M and Goldspink, G. Expression and splicing of the insulin-like growth factor gene in rodent muscle is associated with muscle satellite (stem) cell activation following local tissue damage. J Physiol 549: 409–418, 2003.
2. Izquierdo, M, Ibanez, J, Gonzalez-Badillo, JJ,Hakkinen, K, Ratamess, NA, Kraemer, WJ, French, DN, Eslava, J, Altadill, A,Asiain, X, and Gorostiaga, EM. Differential effects of strength training leading to failure versus not to failure on hormonal responses, strength and muscle power increases. J Appl Physiol 100: 1647–1656, 2006.
3. Evans, WJ. Effects of exercise on senescent muscle. Clin Orthopaed Rel Res 403(Suppl.): S211–S220, 2002.
4. Tee JC, Bosch AN, Lambert MI (2007). Metabolic consequences of exercise induced muscle damage. Sports Med 37: 827-836.
5. Evans WJ. Effects of exercise on senescent muscle. Clin Orthop Relat Res 403(Suppl): S211–S220, 2002.
6. Hill M and Goldspink G. Expression and splicing of the insulin-like growth factor gene in rodent muscle is associated with muscle satellite (stem) cell activation following local tissue damage. J Physiol 549:409–418, 2003.
7. Crameri RM, Langberg H, Magnusson P, Jensen CH,Schroder HD, Olesen JL, and Kjaer M. Changes in satellite cells in human skeletal muscle after a single bout of high intensity exercise. J Physiol 558:333–340, 2004.
8. Yu JG and Thornell LE. Desmin and actin alterations in human muscles affected by delayed onset muscle soreness: A high resolution immunocy to chemical study. Histochem Cell Biol 118: 171–179, 2002.
9. Warren,G. L. Ingalls, C.P. Lowe, D.A. Armstrong, R.B. (2001). Excitation-contraction uncoupling: major role in contraction-induced muscle injury. Exercise and Sport Sciences Reviews 29, 82–87.
10. Morgan, D. L. (1990). New insights into the behavior of muscle during active lengthening. Biophysics Journal 57,209–221.
11. Talbot, J. A. & Morgan, D. L. (1996). Quantitative analysis of sarcomere non-uniformities in active muscle following a stretch. Journal of Muscle Research and Cell Motility 17,261–268.
12. U. Proske D. L. Morgan. Muscle damage from eccentric exercise: mechanism, mechanical signs,adaptation and clinical applications. Journal of Physiology (2001),537.2, pp.333–345
13. Takekura H., Fujinami, N., Nishizawa, T., Ogasawara,H. & Kasuga, N. (2001). Eccentric exercise-induced morphological changes in the membrane systems involved in excitation– contraction coupling in rat skeletal muscle. Journal of Physiology 533, 571–583.
14. Crenshaw AG, Karlsson S, Styf J, et al. Knee extension torque and intramuscular pressure of the vastus lateralis muscle during eccentric and concentric activities. Eur J Appl Physiol 1995;70:13–19.
15. Westing SH, Cresswell AG, Thortensson A. Muscle activation during maximal voluntary exercise and concentric knee extension. EurJ Appl Physiol 1991;62:104–8.
16. Westing SH, Seger JY. Eccentric and concentric torque velocity characteristics, torque output comparisons and gravity effect torque corrections for the quadriceps and hamstring muscles in females. Int J Sports Med 1989;10:175–80
17. Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR,Goodman A, McLafferty CL, and Urban RJ. Mechanical load increases muscle IGF-1and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab 280: E383–E390, 2001
18. Hather BM, Tesch PA, Buchanan P, et al. Influence of eccentric actions on skeletal muscle adaptations to resistance training. Acta Physiol Scand 1991;143:177–85
19. Goldberg AL, Etlinger JD, Goldspink DF, et al. Mechanism of work-induced hypertrophy of skeletal muscle. Med Sci Sports Exerc1975;7:185–98.
20. M Roig, K. O’Brien, G. Kirk, R. Murray, P.McKinnon, B. Shadgan,W. D. Reid. The effects of eccentric versus concentric resistance training on muscle strength and mass in healthy adults: a systematic review with meta-analysis, Br J Sports Med 2009; 43:556–568.
21. Nardone A, Romano, C, and Schieppati M. Selective recruitment of high-threshold human motor units during voluntary isotonic lengthening of active muscles. J Physiol 409: 451–471, 1989.
22. Shepstone TN, Tang JE, Dallaire S, Schuenke MD,Staron RS, and Phillips SM. Short-term high- vs. low-velocity isokinetic lengthening training results in greater hypertrophy of the elbow flexors in young men. J Appl Physiol 98: 1768–1776, 2005.
23. Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, and Ishii N. Effects of resistance exercise combined with moderate vascular occlusion on muscular function in humans. J Appl Physiol 88:2097–2106, 2000.
24. McHugh MP, Connolly DA, Eston RG, and Gleim GW. Electromyographic analysis of exercise resulting in symptoms of muscle damage. J Sport Sci 18: 163–172, 2000.
25. Hortoba´ gyi, T, Barrier J, Beard D, Braspennincx J, and Koens J. Greater initial adaptations to submaximal muscle lengthening than maximal shortening. J Appl Physiol 81: 1677–1682, 1996
26. Kosek DJ, Kim JS, Petrella JK, Cross JM, and Bamman MM. Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults. J Appl Physiol 101: 531–544,2006.
27. Tesch PA. Skeletal muscle adaptations consequent to long-term heavy resistance exercise. Med Sci Sports Exerc 20(5 Suppl):S132–S134, 1988.
28. Toigo, M and Boutellier, U. New fundamental resistance exercise determinants of molecular and cellular muscle adaptations. Eur J Appl Physiol 97: 643–663, 2006.
29. Farthing JP and Chilibeck PD. The effects of eccentric and concentric training at different velocities on muscle hypertrophy. Eur J Appl Physiol 89: 578–586, 2003.
30. Friedmann B, Kinscherf R, Vorwald S, Muller, H,Kucera K, Borisch S, Richter G, Ba¨ rtsch P, and Billeter R. Muscular adaptations to computer-guided strength training with eccentric overload. Acta Physiol Scand 182: 77–88, 2004.
31. Higbie EJ, Cureton KJ, Warren GL III, and Prior BM. Effects of concentric and eccentric training on muscle strength, cross-sectional area, and neural activation. J Appl Physiol 81: 2173–2181, 1996.
32. Norrbrand L, Fluckey JD, Pozzo M, and Tesch PA.Resistance training using eccentric overload induces early adaptations inskeletal muscle size. Eur J Appl Physiol 102: 271–281, 1989.
33. Hather BM, Tesch PA, Buchanan P, and Dudley GA. Influence of eccentric actions on skeletal-muscle adaptations to resistance training. Acta Physiol Scand 143: 177–185, 1991.
34. Eliasson J, et al. Maximal lengthening contractions increase p70 S6 kinase phosphorylation in human skeletal muscle in the absence of nutritional supply. Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1197-205.
35. O'Neil TK, et al. The role of phosphoinositide 3-kinase and phosphatidic acid in the regulation of mammalian target of rapamycin following eccentric contractions. J Physiol. 2009 Jul 15;587 (Pt 14):3691-701.
36. Rosenblatt JD, et al. Satellite cell activity is required for hypertrophy of overloaded adult rat muscle. Muscle Nerve. 1994Jun;17(6):608-13.
37. Bamman MM, et al. Cluster analysis tests the importance of myogenic gene expression during myofiber hypertrophy in humans. J Appl Physiol (1985).2007 Jun;102(6):2232-9.
38. Petrella JK, et al. Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J Appl Physiol (1985). 2008 Jun;104(6):1736-42.
39. Moore DR, Phillips SM, Babraj JA, Smith K, and Rennie MJ. Myofibrillar and collagen protein synthesis in human skeletal muscle in young men after maximal shortening and lengthening contractions. Am J Physiol Endocrinol Metabol 288: E1153–E1159, 2005.
40. Shepstone TN, Tang JE, Dallaire S, Schuenke MD,Staron RS, and Phillips SM. Short-term high- vs. low-velocity isokinetic lengthening training results in greater hypertrophy of the elbow flexors inyoung men. J Appl Physiol 98: 1768–1776, 2005.
41. Eliasson J, Elfegoun T, Nilsson J, Kohnke R,Ekblom B, and Blomstrand E. Maximal lengthening contractions increase p70 S6kinase phosphorylation in human skeletal muscle in the absence of nutritionalsupply. Am J Physiol Endocrinol Metabol 291:E1197–E1205, 2006.
42. Moore DR, et al. Myofibrillar and collagen protein synthesis in human skeletal muscle in young men after maximal shortening and lengthening contractions. Am J Physiol Endocrinol Metab. 2005 Jun; 288(6):E1153-9.
43. Shepstone TN, et al. Short-term high- vs. low-velocity isokinetic lengthening training results in greater hypertrophy of the elbow flexors in young men. J Appl Physiol (1985). 2005 May; 98(5):1768-76.
44. Schoenfeld BJ. The mechanisms of muscle hypertrophy and their application to resistance training. J Strength Cond Res24: 2857–2875, 2010.
45. Macintyre, D. L., Reid, W. D. & Mckenzie, D.C. (1995). Delayed muscle soreness. The inflammatory response to muscle injury and its clinical implications. Journal of Sports Medicine 20,24–40.
46. Hough, T. (1902). Ergographic studies in muscular soreness. American Journal of Physiology 7, 76–92.
47. Byrne C, Twist C, Eston R. Neuromuscular function after exercise-induced muscle damage. Sports Med 2004;34:49–69.
48. Jones, C., Allen, T., Talbot, J., Morgan, D. L.& Proske, U. (1997). Changes in the mechanical properties of human and amphibian muscle after eccentric exercise. European Journal of Applied Physiology and Occupational Physiology 76, 21–31.
49. Smith, L. L. (1991). Acute inflammation: the underlying mechanism in delayed onset muscle soreness? Medicine and Science inSports and Exercise 23, 542–551.
50. Barlas, P., Walsh, D. M., Baxter, G. D. & Allen,J. M. (2000). Delayed onset muscle soreness: effect of an ischaemic block upon mechanical allodynia in humans. Pain 87, 221–225.
51. Weerakkody, N. S. Whitehead, N.P. Canny, B. J.Gregory J. E. & Proske. (2001). Large-fiber mechano receptors contribute to muscle soreness after eccentric exercise. Journal of Pain 2,209–219.
52. Moir GL, Erny KF, Davis SE, Guers JJ, Witmer CA.The Development of a Repetition-Load Scheme for the Eccentric-Only Bench Press Exercise. J Hum Kinet. 2013 Oct 8;38:23-31.
53. Brad Schoenfeld. The Use of Specialized Training Techniques to Maximize Muscle Hypertrophy. Strength & Conditioning Journal: August 2011 - Volume 33 - Issue 4 - pp 60-65
54. Mayhew TP, et al. Muscular adaptation to concentric and eccentric exercise at equal power levels. Med Sci Sports Exerc.1995 Jun;27(6):868-73.
55. Mitchell CJ, Churchward-Venne TA, Parise G, Bellamy L, Baker SK, et al. (2014) Acute Post-Exercise Myofibrillar Protein Synthesis Is Not Correlated With Resistance Training-Induced Muscle Hypertrophy in Young Men. PLoS ONE 9(2): e89431. 
56. Cameron J. Mitchell , Tyler A. Churchward-Venne , David Cameron-Smith , Stuart M. Phillips. What is the relationship between the acute muscle protein synthetic response and changes in muscle mass? Journal of Applied PhysiologyPublished 25 September 2014