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Chad Workman December 4, 2011 EXP 501 EXP 501 Hallmark Paper: Mechanisms of Muscle Hypertrophy and their Indications on Exercise Program Variables Exercise is widely researched and practiced in efforts to improve health and performance. It has been shown that exercise training can induce a physiologic response that will favor adaptation to an imposed demand. The principle of specificity states that these adaptations will be specific the demand imposed. This suggests that different modalities of exercise training will produce different physiological responses both acute and chronically. Hypertrophy is a term used to describe the increase in cross sectional area (CSA) of a muscle. Increases in lean body mass have long been pursued by recreational exercisers for aesthetic reasons as well as the well documented improvements in muscular strength associated with increases in CSA (1,2,3,4). Muscle Hypertrophy is also associated with improvements in performance of strength and power sports such as Football, Track and Field, Rugby, Weightlifting, Power-lifting, and Bodybuilding to name a few (1,4). This association of improvements in strength and power output favor the proposal that improvements in CSA could be advantageous to athletes involved in most sporting activities, especially those that involve large amounts of mechanical tension developed within a muscle. These correlations also suggest that the hypertrophy of muscle should be a pursuit of all individuals in an effort to improve health. Hypertrophy can describe and occur via multiple physical changes to the structure and/or content of a muscle. “Contractile Hypertrophy” describes an increase in the size of the contractile proteins “Myosin and Actin” which are widely accepted as the proteins responsible for mechanical shortening of a sarcomere (6). Contractile Hypertrophy can happen by adding sarcomeres to the individual myofibrils in length or in parallel. Chronic elongation of muscles as Chad Workman December 4, 2011 EXP 501 well as eccentric based resistance training has been shown to increase sarcomeres in series (7,8). Concentric resistance training is associated with adding sarcomeres in series (8). These concepts have implications on the type of training performed and concomitant increases in performance. An increase in the volume of the sarcoplasm of a muscle cell has been coined “sarcoplasmic hypertrophy” and is often considered non-functional, unlike contractile hypertrophy, because of the lack of structural change to the contractile elements of the cell (3). However, some research suggests that increase in cell volume can stimulate other factors important to the structural integrity of the cell as well as increase the amount of anabolic molecules within the sarcoplasm (2). Hyperplasia is a term used to describe an increase in the total number of fibers contained within a muscle and should be considered different than hypertrophy. There is conflicting evidence within the academia and literature that hyperplasia occurs in humans (2). Some animal studies have shown hyperplasia in response to exercise, but a conclusion is yet to be drawn in research on humans. Satellite Cells are an important factor in maintaining the homeostasis of a muscle cell. These cells are thought to be the main mediators of muscle hypertrophy. They are located between the basal lamina and the sarcolemma (2). Normally inactive, Satellite cells need some sort of chemical or mechanical stimulus to become activated. Once activated, they bind to cells and provide means that are necessary for hypertrophy (8). Satellite cells donate nuclei to the muscle cells which can increase the protein synthesis of the cell. Furthermore, a muscle retains a constant nuclear-content-to-fiber-mass ratio and thus an increase in either would mediate and require an increase in the other (182). There are also multiple myogenic pathways of muscle hypertrophy. These pathways include a chemical response to a mechanical stimulus that will travel downstream to exert an Chad Workman December 4, 2011 EXP 501 anabolic effect on the muscle cell by promoting muscle hypertrophy or inhibiting catabolism. Akt/Mammalian Target Rapamycin Pathway is an important mediator of protein synthesis and breakdown (2,9). Akt is stimulated by mechanical stress which signals (Target of Rapamycin) mTOR farther downstream that will have anabolic effects on muscle cells (2,9). The Mitogen Activated Protein Kinase (MAPK) pathway is a mediator of adaptive response to a stressor. This occurs by increasing mRNA transcription and DNA repair (2). There are also other Calcium dependent pathways in which Calcineurin (Cn) signals other factors that play a crucial role in hypertrophic response (2). Hormones are long-distance, long-acting communicators of the body. They usually have one or more of three different effects on a cell: 1) Alter membrane transport of the cell. 2) Alter DNA activity of the cell. 3) Activate second messengers within the cell to elicit an effect (18). Steroid hormones are commonly associated with muscle hypertrophy and strength, but there are many other and maybe even more important hormones involved in hypertrophy that are not steroids. To discuss every hormone that is involved in hypertrophy would be impractical for this paper and so a brief overview of some important hormones will be discussed. Testosterone is a sex hormone that is produced and secreted primarily from the testes in men and ovaries in women. Its production and release is stimulated by Luetinizing Stimulating Hormone released by the Anterior Pituitary Gland. A post-exercise spike in testosterone has been observed in men, especially after resistance training, but not to the same extent in women (11,12). Testosterone binds to its particular receptors on the cell and stimulates protein synthesis within the cell. Furthermore, an abundance of testosterone has shown to increase the number of active receptor cites on the cell exhibiting a positive feedback that could have implications on a chronic Chad Workman December 4, 2011 EXP 501 adaptation to resistance training that favors hypertrophy. High levels of testosterone stimulate the production and release of Growth Hormone which is be discussed later (13). Insulin-like-growth factor (IGF-1) is perhaps the most important hormonal regulator of anabolism. IGF-1 acts on active Satellite cells and Schwann cells. Its name comes from its structural similarity to Insulin. It is produced by muscles in greater quantities during exercise and is particularly sensitive to muscle damage (10). The isoform IGF- 1Ec is also called “mechano-growth-factor” (MGF) which is the isoform that is more sensitive to mechanical tension, particularly eccentric exercise and directly acts to increase protein synthesis (2). IGF-1 is also implicated in the mitotic activity of satellite cells as well as the binding of satellite cells to muscle cells (2), thus playing a factor in increasing the number of nuclei in the muscle cell and in turn enhancing protein synthesis. Growth Hormone (GH) is another highly active regulator of overall tissue growth. It is produced in the Hypothalamus and released from the Anterior Pituitary gland. Unlike other hormones, GH exerts its effects on connective tissue and bone stimulating growth on both. Growth Hormone is also active in metabolic activity. GH has been shown to increase the mobilization of triglycerides from fat cells and increase the cellular uptake of amino acids. Spikes in Growth Hormone are shown post exercise of multiple types and have been implicated in the hypertrophic response to mechanical loading (2,13). High levels of GH influence IGF-1 to the isoform MGF (2). Insulin is another important hormone with anabolic properties. Released from the pancreas in response to increased levels of blood glucose, insulin acts to alter the transport of molecules across cell membranes. Most commonly associated with glucose uptake, insulin also Chad Workman December 4, 2011 EXP 501 increases uptake of amino acids and free fatty acids (18). Increases in amino acids within the cell are necessary to carry out the protein synthesis needed for hypertrophic changes. Insulin is usually inhibited during exercise (18). A spike of insulin post-exercise along with an adequate amount of the right amino acids along with the previously mentioned factors could lead to muscle hypertrophy. Mechanical Tension, muscle damage, and metabolic stress are a byproduct of resistance training and are important stimuli of the above mentioned pathways of hypertrophy (1,2,3,14,15,16). This damage usually occurs via an abnormal level of tension being created by voluntary contraction. Long periods of high levels of tension are associated with very high metabolic demands, primarily via the depletion of muscle phosphocreatine and stored glycogen. These metabolic demands are associated with high levels of lactate accumulation and other byproducts of glycogenolysis (16). These homeostatic disturbances have also shown to be a stimulus of the hypertropic response of hormones, myogenic pathways, and the activity of satellite cells. Sarcoplasmic hypertrophy is an increase in the volume of the cytoplasm of a muscle cell. This can be accomplished thorough multiple means. Since most of the cytoplasmic volume is water, you can manipulate the amount of specific solutes within the cell that will influence the water level within the cell. The most common method is to increase the amount of glucose within the cell. Other ions can play a role in this as well, however since these ions play a role in the membrane potential and action potential of the cell, manipulating these concentrations could prove to negatively influence performance. Competitive bodybuilders manipulate Sodium and Glucose concentrations in an effort to appear larger and leaner. Competitive endurance athletes also make attempts to maximize muscle glucose stores by “carbohydrate loading”, but not in an Chad Workman December 4, 2011 EXP 501 attempt to increase muscularity. Instead, their purpose is to improve performance by providing more substrate to produce ATP via glycolysis. The load imposed by increases in intracellular volume on the cell membrane could potentially lead to adaptations in cell membrane strength and improve performance. Also, the increase in the total amount of molecules within a cell could provide for a greater pool of nutrients to exert hypertrophic pathways (3). From the data presented above, one can come to some conclusions of how to elicit muscle hypertrophy. Most of the factors listed are related to variables that can be manipulated in training. Mechanical tension is needed to elicit hypertrophy. This tension has to be high to elicit hypertrophy though. This is why endurance athletes that spend large amounts of time under tension, albeit low, do not show significant hypertrophy. This is also why low load, high volume resistance training has not been shown to extensively stimulate hypertrophy (2,3). A sufficient amount of time has to be spent under this high level of tension. This is one explanation why very high load, low volume training does not always elicit the same levels of hypertrophy as moderate load, moderate intensity training (1,2,3). As mentioned before, metabolic stress can stimulate hypertrophy (17). This alone is not sufficient enough to increase hypertrophy though, which is also observable in the previous example of endurance athletes. Although there is a high level of glycolytic metabolic stress, especially in biking events and mid distance runners, there is not a hypertrophic response. Considering all of the pathways, training to elicit hypertrophy should entail high levels of tension and an adequate amount of time spent at that tension. This would cause considerable muscle damage as well as metabolic stress. High load eccentric training and high load isometric training are both non-traditional methods that would fit these requirements. Other methods could be simply accumulating enough repetitions under a moderate load to elicit hypertrophy. This is Chad Workman December 4, 2011 EXP 501 what has made up several training methodologies including: HIT, bodybuilding split training, German volume training, Escalating Density Training (EDT), etc. While the area of hypertrophy has been widely researched, certain aspects of training response are not totally clear. It is likely that responses to training will vary between individuals due to genetic differences and other behavior factors. However, extensive research has shown consistent commonalities between specific modalities of training and the proposed methods of training listed above would be an appropriate prescription of training for those seeking muscle hypertrophy. 1. Zatsiorsky, VM. Science and Practice of Strength Training. Champaign, IL: Human Kinetics, 1995. 2. Schoenfeld, B. The Mechanisms of Muscle Hypertrophy and Their Application to Resistance Training. Journal of Strength and Conditioning Research. 24(10), 2857-2872, 2010. 3. Siff, MC and Verhoshanksy, YV. Supertraining (4th ed.).Denver, CO. Supertraining International. 4. Maughan, RJ, Watson, JS, and Weir, J. Strength and cross-sectional area of human skeletal muscle. J Physiol 338: 37–49, 1983. 5. Bickel, CS, Slade, J, Mahoney, E, Haddad, F, Dudley, GA, and Adams, GR. Time course of molecular responses of human skeletal muscle to acute bouts of resistance exercise. J Appl Physiol 98: 482–488, 2005. 6. Paul, AC and Rosenthal, N. Different modes of hypertrophy in skeletal muscle fibers. J Cell Biol 18: 156: 751–760, 2002. 7. Lynn, R and Morgan, DL. Decline running produces more sarcomeres in rat vastus intermedius muscle fibers than does incline running. J Appl Physiol 77: 1439–1444, 1994. 8. Toigo, M and Boutellier, U. New fundamental resistance exercise determinants of molecular and cellular muscle adaptations. Eur J Appl Physiol 97: 643–663, 2006. 9. Bodine, SC, Stitt, TN, Gonzalez, M, Kline, WO, Stover, GL, Bauerlein, R, Zlotchenko, E, Scrimgeour, A, Lawrence, JC, Glass, DJ, and Yancopoulos, GD. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3: 1014–1019, 2001. 10. Brahm, H, Pehl-Aulin, K, Saltin, B, and Ljunghall, S. Net fluxes over working thigh of hormones, growth factors and biomarkers of bone metabolism during short lasting dynamic exercise. Calc Tiss Int 60: 175–180, 1997. 11. Ahtiainen, JP, Pakarinen, A, Alen, M, Kraemer, WJ, and Ha¨kkinen, K. Muscle hypertrophy, hormonal adaptations and strength development during strength training in strength-trained and untrained men. Eur J Appl Physiol 89: 555–563, 2003. 12. Ha¨kkinen, K, Pakarinen, A, Kraemer, WJ, Newton, RU, and Alen, M. Basal concentrations and acute responses of serum hormones and strength development during Chad Workman December 4, 2011 EXP 501 heavy resistance training in middle-aged and elderly men and women. J Gerontol. Ser A, Biol Sci Med Sci 55: B95–B105, 2000. 13. Crewther, B, Keogh, J, Cronin, J, and Cook, C. Possible stimuli for strength and power adaptation: Acute hormonal responses. Sport Med 36: 215–238, 2006. 14. Evans, WJ. Effects of exercise on senescent muscle. Clin Orthopaed Rel Res 403(Suppl.): S211–S220, 2002. 15. Goldspink, G. Gene expression in skeletal muscle. Biochem Soc Trans 30: 285–290, 2002. 16. Rooney, KJ, Herbert, RD, and Balnave, RJF. Fatigue contributes to the strength training stimulus. Med Sci Sport Exerc 26: 1160–1164, 1994. 17. Folland, JP, Irish, CS, Roberts, JC, Tarr, JE, and Jones, DA. Fatigue is not a necessary stimulus for strength gains during resistance training. Br J Sports Med 36: 370–373, 2002. 18. Powers S, Howley E. Exercise Physiology: Theory and Application to Fitness and Performance. McGraw Hill. New York, NY. 2009.