The mechanisms of muscle hypertrophy and their application to resistance training

Abstract

<h2>Abstract</h2> <p>The quest to increase <a href="/terms/lean-body-mass/" class="term-link" data-slug="lean-body-mass" title="lean body mass">lean body mass</a> is widely pursued by those who lift weights. Research is lacking, however, as to the best approach for maximizing exercise-induced muscle growth. Bodybuilders generally train with moderate loads and fairly short rest intervals that induce high amounts of <a href="/terms/metabolic-stress/" class="term-link" data-slug="metabolic-stress" title="metabolic stress">metabolic stress</a>. Powerlifters, on the other hand, routinely train with high-intensity loads and lengthy rest periods between sets. Although both groups are known to display impressive muscularity, it is not clear which method is superior for hypertrophic gains. It has been shown that many factors mediate the hypertrophic process and that <a href="/terms/mechanical-tension/" class="term-link" data-slug="mechanical-tension" title="mechanical tension">mechanical tension</a>, <a href="/terms/muscle-damage/" class="term-link" data-slug="muscle-damage" title="muscle damage">muscle damage</a>, and metabolic stress all can play a role in exercise-induced muscle growth. Therefore, the purpose of this paper is twofold: (a) to extensively review the literature as to the mechanisms of <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="muscle hypertrophy">muscle hypertrophy</a> and their application to exercise training and (b) to draw conclusions from the research as to the optimal protocol for maximizing muscle growth.</p>

Introduction

<h2>Introduction</h2> <p>The quest to increase <a href="/terms/lean-body-mass/" class="term-link" data-slug="lean-body-mass" title="lean body mass">lean body mass</a> is widely pursued by those who lift weights. Given the strong correlation between muscle <a href="/terms/cross-sectional-area/" class="term-link" data-slug="cross-sectional-area" title="cross-sectional area">cross-sectional area</a> and muscular strength [111], increased muscle mass is a primary goal of athletes involved in strength and power sports such as football, rugby, and powerlifting. Muscle mass also is vital to the sport of bodybuilding, where competitors are judged on both the quantity and quality of their muscle development. On a more general level, <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="muscle hypertrophy">muscle hypertrophy</a> is also pursued by the many recreational lifters who aspire to develop their physiques to the fullest. Therefore, the maximization of muscle mass has far reaching implications to a variety of populations associated with sports and health.</p> <p>In untrained subjects, muscle hypertrophy is virtually nonexistent during the initial stages of resistance training, with the majority of strength gains resulting from neural adaptations [124]. Within a couple of months of training, however, hypertrophy begins to become the dominant factor, with the upper extremities shown to hypertrophy before the lower extremities [124, 177]. Genetic background, age, gender, and other factors have been shown to mediate the hypertrophic response to a training protocol, affecting both the rate and the total amount of gains in lean muscle mass [93]. Further, it becomes progressively more difficult to increase lean muscle mass as one gains training experience, heightening the importance of proper routine design.</p> <p>Although muscle hypertrophy can be attained through a wide range of resistance training programs, the principle of specificity dictates that some routines will promote greater hypertrophy than others [16]. Research is lacking, however, as to the best approach for achieving this goal. Bodybuilders generally train with moderate loads and fairly short rest intervals that induce high amounts of <a href="/terms/metabolic-stress/" class="term-link" data-slug="metabolic-stress" title="metabolic stress">metabolic stress</a>. Powerlifters, on the other hand, routinely train with high-intensity loads and lengthy rest periods between sets. Although both groups are known to display impressive muscularity, it is not clear which method is best for maximizing hypertrophic gains [149] or whether other training methods may perhaps be superior. Therefore, the purpose of this paper is twofold: (a) to extensively review the literature as to the mechanisms of muscle hypertrophy and their application to resistance training variables and (b) to draw conclusions from the research and develop a hypertrophy-specific routine for maximizing muscle growth.</p>

Types of Muscle Hypertrophy

<h2>Types of <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="Muscle Hypertrophy">Muscle Hypertrophy</a></h2> <p>Muscle hypertrophy can be considered distinct and separate from muscle hyperplasia. During hypertrophy, contractile elements enlarge and the extracellular matrix expands to support growth [187]. This is in contrast to hyperplasia, which results in an increase in the number of fibers within a muscle. <a href="/terms/myofibrillar-hypertrophy/" class="term-link" data-slug="myofibrillar-hypertrophy" title="Contractile hypertrophy">Contractile hypertrophy</a> can occur either by adding sarcomeres in series or in parallel.</p> <p>The majority of exercise-induced hypertrophy subsequent to traditional resistance training programs results from an increase of sarcomeres and myofibrils added in parallel [135, 179]. When skeletal muscle is subjected to an overload stimulus, it causes perturbations in myofibers and the related extracellular matrix. This sets off a chain of myogenic events that ultimately leads to an increase in the size and amounts of the myofibrillar contractile proteins actin and myosin, and the total number of sarcomeres in parallel. This, in turn, augments the diameter of individual fibers and thereby results in an increase in muscle <a href="/terms/cross-sectional-area/" class="term-link" data-slug="cross-sectional-area" title="cross-sectional area">cross-sectional area</a> [182].</p> <p>A serial increase in sarcomeres results in a given muscle length corresponding to a shorter <a href="/terms/sarcomere/" class="term-link" data-slug="sarcomere" title="sarcomere">sarcomere</a> length [182]. In-series hypertrophy has been shown to occur when muscle is forced to adapt to a new functional length. This is seen with limbs that are placed in a cast, where immobilization of a joint at long muscle lengths results in an increased number of sarcomeres in series, whereas immobilization at shorter lengths causes a reduction [182]. There is some evidence that certain types of exercise can affect the number of sarcomeres in series. Lynn and Morgan [107] showed that when rats climbed on a treadmill (i.e., incline), they had a lower sarcomere count in series than those who descended (i.e., decline). This suggests that repeated eccentric-only actions lead to a greater number of sarcomeres in series, whereas exercise consisting solely of concentric contractions results in a serial decrease in sarcomere length.</p> <p>It is hypothesized that hypertrophy may be augmented by an increase in various noncontractile elements and fluid [108, 205]. This has been termed "<a href="/terms/sarcoplasmic-hypertrophy/" class="term-link" data-slug="sarcoplasmic-hypertrophy" title="sarcoplasmic hypertrophy">sarcoplasmic hypertrophy</a>," and may result in greater muscle bulk without concomitant increases in strength [154]. Increases in sarcoplasmic hypertrophy are thought to be training specific, a belief perpetuated by studies showing that muscle hypertrophy is different in bodybuilders than in powerlifters [179]. Specifically, bodybuilders tend to display a greater proliferation of fibrous endomysial <a href="/terms/connective-tissue/" class="term-link" data-slug="connective-tissue" title="connective tissue">connective tissue</a> and a greater glycogen content compared to powerlifters [109, 177], presumably because of differences in training methodology. Although sarcoplasmic hypertrophy is often described as nonfunctional, it is plausible that chronic adaptations associated with its effects on cell swelling may mediate subsequent increases in <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="protein synthesis">protein synthesis</a> that lead to greater contractile growth.</p> <p>Some researchers have put forth the possibility that increases in cross-sectional area may be at least partly because of an increase in fiber number [8]. A meta-analysis by Kelley [84] found that hyperplasia occurs in certain animal species under experimental conditions as a result of <a href="/terms/mechanical-tension/" class="term-link" data-slug="mechanical-tension" title="mechanical overload">mechanical overload</a>. However, subsequent research suggests that such observations may be erroneous, with results attributed to a miscounting of the intricate arrangements of elongating fibers as a greater fiber number [135]. Evidence that hyperplasia occurs in human subjects is lacking and, if it does occur at all, the overall effects on muscle cross-sectional area would appear to be minimal [1, 108].</p>

Satellite Cells and Muscle Hypertrophy

<h2><a href="/terms/satellite-cells/" class="term-link" data-slug="satellite-cells" title="Satellite Cells">Satellite Cells</a> and <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="Muscle Hypertrophy">Muscle Hypertrophy</a></h2> <p>Muscle is a postmitotic tissue, meaning that it does not undergo significant cell replacement throughout life. An efficient method for cell repair is therefore required to avoid apoptosis and maintain skeletal mass. This is carried out through the dynamic balance between <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="muscle protein synthesis">muscle protein synthesis</a> and degradation [69, 182]. Muscle hypertrophy occurs when protein synthesis exceeds protein breakdown.</p> <p>Hypertrophy is thought to be mediated by the activity of satellite cells, which reside between the basal lamina and sarcolemma [66, 146]. These "myogenic stem cells" are normally quiescent but become active when a sufficient mechanical stimulus is imposed on skeletal muscle [187]. Once aroused, satellite cells proliferate and ultimately fuse to existing cells or among themselves to create new myofibers, providing the precursors needed for repair and subsequent growth of new muscle tissue [182].</p> <p>Satellite cells are thought to facilitate muscle hypertrophy in several ways. For one, they donate extra nuclei to muscle fibers, increasing the capacity to synthesize new contractile proteins [123]. Because a muscle's nuclear-content-to-fiber-mass ratio remains constant during hypertrophy, changes require an external source of mitotically active cells. Satellite cells retain mitotic capability and thus serve as the pool of <a href="/terms/myonuclei/" class="term-link" data-slug="myonuclei" title="myonuclei">myonuclei</a> to support muscle growth [15]. This is consistent with the concept of myonuclear domain, which proposes that the myonucleus regulates mRNA production for a finite sarcoplasmic volume and any increases in fiber size must be accompanied by a proportional increase in myonuclei. Given that muscles are comprised of multiple myonuclear domains, hypertrophy could conceivably occur as a result of either an increase in the number of domains (via an increase in myonuclear number) or an increase in the size of existing domains. Both are thought to occur in hypertrophy, with a significant contribution from satellite cells [182].</p> <p>Moreover, satellite cells coexpress various myogenic regulatory factors (including Myf5, MyoD, myogenin, and MRF4) that aid in muscle repair, regeneration, and growth [27]. These regulatory factors bind to sequence specific DNA elements present in the muscle gene promoter, with each playing distinct roles in myogenesis [148, 155].</p>

Myogenic Pathways

<h2>Myogenic Pathways</h2> <p>Exercise-induced <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="muscle hypertrophy">muscle hypertrophy</a> is facilitated by a number of signaling pathways, whereby the effects of mechano-stimulation are molecularly transduced to downstream targets that shift muscle protein balance to favor synthesis over degradation. Several primary anabolic signaling pathways have been identified including Akt/<a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mammalian target of rapamycin">mammalian target of rapamycin</a> (mTOR), mitogen-activated protein kinase (MAPK), and calcium-(Ca2+) dependent pathways.</p> <h3>Akt/Mammalian Target of Rapamycin Pathway</h3> <p>The Akt/mTOR pathway is believed to act as a master network regulating skeletal muscle growth [18, 77, 181]. Although the specific molecular mechanisms have not been fully elucidated, Akt is considered a molecular upstream nodal point that is both an effector of anabolic signaling and a dominant inhibitor of catabolic signals [126, 182]. When activated, Akt signals mTOR, which then exerts effects on various downstream targets that promote hypertrophy in muscle tissue.</p> <h3>Mitogen-Activated Protein-Kinase Pathway</h3> <p>Mitogen-activated protein kinase (MAPK) is considered a master regulator of gene expression, redox status, and metabolism [88]. Specific to exercise-induced skeletal muscle hypertrophy, MAPK has been shown to link cellular stress with an adaptive response in myocytes, modulating growth and differentiation [147]. Three distinct MAPK signaling modules are associated with exercise-induced muscle hypertrophy: extracellular signal-regulated kinases (ERK 1/2), p38 MAPK, and c-Jun NH2–terminal kinase (JNK). Of these modules, JNK has shown to be the most responsive to <a href="/terms/mechanical-tension/" class="term-link" data-slug="mechanical-tension" title="mechanical tension">mechanical tension</a> and <a href="/terms/muscle-damage/" class="term-link" data-slug="muscle-damage" title="muscle damage">muscle damage</a>, and it is particularly sensitive to eccentric exercise. Exercise-induced activation of JNK has been linked to a rapid rise in mRNA of transcription factors that modulate cell proliferation and DNA repair [9, 10].</p> <h3>Calcium-Dependent Pathways</h3> <p>Various Ca2+-dependent pathways have been implicated in the regulation of muscle hypertrophy. Calcineurin (Cn), a Ca2+-regulated phosphatase, is believed to be a particularly critical regulator in the Ca2+ signaling cascade. Cn acts downstream in the Ca2+ pathway and mediates various hypertrophic effectors such as <a href="/terms/muscle-fiber/" class="term-link" data-slug="muscle-fiber" title="myocyte">myocyte</a> enhancing factor 2, GATA transcription factors, and nuclear factor of activated T cells [118]. Cn-dependent signaling is linked to hypertrophy of all fiber types, and its inhibition has been shown to prevent muscle growth even in the presence of muscular overload [35, 36].</p> <h3>Hormones and Cytokines</h3> <p>Hormones and cytokines play an integral role in the hypertrophic response, serving as upstream regulators of anabolic processes. Elevated anabolic hormone concentrations increase the likelihood of receptor interactions, facilitating protein metabolism and subsequent muscle growth [31]. Many are also involved in satellite cell proliferation and differentiation and perhaps facilitate the binding of <a href="/terms/satellite-cells/" class="term-link" data-slug="satellite-cells" title="satellite cells">satellite cells</a> to damaged fibers to aid in muscular repair [182, 187].</p> <p><strong>Insulin-Like Growth Factor.</strong> Insulin-like growth factor (<a href="/terms/igf-1/" class="term-link" data-slug="igf-1" title="IGF-1">IGF-1</a>) is often referred to as the most important mammalian anabolic hormone [19, 63]. Three distinct IGF-1 isoforms have been identified: the systemic forms IGF-1Ea and IGF-1Eb, and a splice variant, IGF-1Ec. Although all 3 isoforms are expressed in muscle tissue, only IGF-1Ec appears to be activated by mechanical signals [63, 199]. Because of its response to mechanical stimulation, IGF-1Ec is familiarly called mechano growth factor (MGF). IGF-1 directly promotes anabolism by increasing the rate of <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="protein synthesis">protein synthesis</a> in differentiated myofibers [15, 63] and activates satellite cells, mediating their proliferation and differentiation [69, 200].</p> <p><strong>Testosterone.</strong> Testosterone is a cholesterol-derived hormone that has a considerable anabolic effect on muscle tissue [33, 105]. Its actions are magnified by mechanical loading, promoting anabolism both by increasing the protein synthetic rate and inhibiting protein breakdown [22]. Testosterone may also contribute to protein accretion indirectly by stimulating the release of other anabolic hormones such as GH [31]. Resistance exercise can have a substantial acute effect on testosterone secretion, with significant correlations found between training-induced elevations in testosterone and muscle <a href="/terms/cross-sectional-area/" class="term-link" data-slug="cross-sectional-area" title="cross-sectional area">cross-sectional area</a> [2].</p> <p><strong>Growth Hormone.</strong> Growth hormone (GH) is a polypeptide hormone considered to have both anabolic and catabolic properties. GH acts as a repartitioning agent to induce fat metabolism toward mobilization of triglycerides and stimulating cellular uptake and incorporation of amino acids into various proteins, including muscle [187]. Growth hormone levels spike after the performance of various types of exercise [96], and an exercise-induced increase in GH has been highly correlated with the magnitude of type I and <a href="/terms/type-ii-muscle-fiber/" class="term-link" data-slug="type-ii-muscle-fiber" title="type II muscle fiber">type II muscle fiber</a> hypertrophy [113].</p>

Mechanical Tension, Muscle Damage, and Metabolic Stress

<h2><a href="/terms/mechanical-tension/" class="term-link" data-slug="mechanical-tension" title="Mechanical Tension">Mechanical Tension</a>, <a href="/terms/muscle-damage/" class="term-link" data-slug="muscle-damage" title="Muscle Damage">Muscle Damage</a>, and <a href="/terms/metabolic-stress/" class="term-link" data-slug="metabolic-stress" title="Metabolic Stress">Metabolic Stress</a></h2> <p>It is hypothesized that 3 primary factors are responsible for initiating the hypertrophic response to resistance exercise: mechanical tension, muscle damage, and metabolic stress [38, 79, 153, 185].</p> <h3>Mechanical Tension</h3> <p>Mechanically induced tension produced both by force generation and stretch is considered essential to muscle growth, and the combination of these stimuli appears to have a pronounced additive effect [48, 72, 185]. Mechanical overload increases muscle mass while unloading results in atrophy [47]. It is believed that tension associated with resistance training disturbs the integrity of skeletal muscle, causing mechanochemically transduced molecular and cellular responses in myofibers and <a href="/terms/satellite-cells/" class="term-link" data-slug="satellite-cells" title="satellite cells">satellite cells</a> [182]. Evidence suggests that the downstream process is regulated via the AKT/<a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mTOR">mTOR</a> pathway, either through direct interaction or by modulating production of phosphatidic acid [72, 73].</p> <p>During eccentric contractions, passive muscular tension develops because of lengthening of extramyofibrillar elements, especially collagen content in extracellular matrix and titin [182]. This augments the active tension developed by the contractile elements, enhancing the hypertrophic response. Both the amplitude and duration of excitation coupling is determined by motor unit (<a href="/terms/motor-unit/" class="term-link" data-slug="motor-unit" title="MU">MU</a>) firing frequency, which is believed to encode signals to various downstream pathways including Ca2+ calmodulin phosphatase calcineurin, CaMKII, and CAMKIV, and PKC [26].</p> <p>Passive tension produces a hypertrophic response that is fiber-type specific, with an effect seen in fast-twitch but not slow-twitch fibers [139]. Although mechanical tension alone can produce <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="muscle hypertrophy">muscle hypertrophy</a>, it is unlikely to be solely responsible for hypertrophic gains associated with exercise [79]. Certain resistance training routines employing high degrees of muscle tension have been shown to largely induce neural adaptations without resultant hypertrophy [28, 188].</p> <h3>Muscle Damage</h3> <p>Exercise training can result in localized damage to muscle tissue which, under certain conditions, is theorized to generate a hypertrophic response [38, 69]. Damage can range from disruption of just a few macromolecules to large tears in the sarcolemma, basal lamina, and supportive <a href="/terms/connective-tissue/" class="term-link" data-slug="connective-tissue" title="connective tissue">connective tissue</a>, and induces injury to contractile elements and the cytoskeleton [187]. Because the weakest sarcomeres are located at different regions of each <a href="/terms/myofibril/" class="term-link" data-slug="myofibril" title="myofibril">myofibril</a>, nonuniform lengthening causes a shearing of myofibrils. This deforms membranes, particularly T-tubules, leading to a disruption of calcium homeostasis and consequently damage because of tearing of membranes and/or opening of stretch-activated channels [4].</p> <p>The response to myotrauma has been likened to the acute inflammatory response to infection. Once damage is perceived by the body, neutrophils migrate to the area of microtrauma and agents are then released by damaged fibers that attract macrophages and lymphocytes. Macrophages remove cellular debris to help maintain the fiber's ultrastructure and produce cytokines that activate myoblasts, macrophages and lymphocytes. This is believed to lead to the release of various growth factors that regulate satellite cell proliferation and differentiation [182, 187]. Furthermore, the area under the myoneural junction contains a high concentration of satellite cells, which have been shown to mediate muscle growth [69, 155].</p> <h3>Metabolic Stress</h3> <p>Numerous studies support an anabolic role of exercise-induced metabolic stress [145, 149, 161] and some have speculated that metabolite accumulation may be more important than high force development in optimizing the hypertrophic response to training [153]. Although metabolic stress does not seem to be an essential component of muscular growth [40], a large body of evidence shows that it can have a significant hypertrophic effect, either in a primary or secondary manner.</p> <p>Metabolic stress manifests as a result of exercise that relies on anaerobic glycolysis for <a href="/terms/adenosine-triphosphate/" class="term-link" data-slug="adenosine-triphosphate" title="ATP">ATP</a> production, which results in the subsequent buildup of metabolites such as lactate, hydrogen ion, inorganic phosphate, <a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="creatine">creatine</a>, and others [169, 178]. Muscle ischemia also has been shown to produce substantial metabolic stress, and potentially produces an additive hypertrophic effect when combined with glycolytic training [136, 182]. The stress-induced mechanisms theorized to mediate the hypertrophic response include alterations in hormonal milieu, cell swelling, free-radical production, and increased activity of growth-oriented transcription factors [50, 51, 171]. It also has been hypothesized that a greater acidic environment promoted by glycolytic training may lead to increased fiber degradation and greater stimulation of sympathetic nerve activity, thereby mediating an increased adaptive hypertrophic response [22].</p> <h3>Cell Swelling and Hypoxia</h3> <p>Cellular hydration (i.e., cell swelling) serves as a physiological regulator of cell function [65] and is known to stimulate anabolic processes, both through increases in <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="protein synthesis">protein synthesis</a> and decreases in proteolysis [53, 120, 165]. A hydrated cell has been shown to initiate a process that involves activation of protein-kinase signaling pathways in muscle, possibly mediating autocrine effects of growth factors in signaling the anabolic response to membrane stretch [106].</p> <p>Hypoxia has been shown to contribute to increases in muscle hypertrophy, with effects seen even in the absence of exercise. When combined with exercise, hypoxia seems to have an additive effect on hypertrophy. There are several theories as to the potential hypertrophic benefits of muscle hypoxia, including increased lactate accumulation, elevated anabolic hormones and cytokines, reactive oxygen species (ROS) production, and reactive hyperemia that delivers anabolic endocrine agents and growth factors to satellite cells [172, 173].</p>