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Journal of Strength and Conditioning Research:


The Mechanisms of Muscle Hypertrophy

In untrained subjects, muscle hypertrophy is virtually non-existent during the initial stages of resistance training, with the majority of strength gains resulting from neural adaptations. 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.

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. Further, it becomes progressively more difficult to increase lean muscle mass as one gains training experience, heightening the importance of proper routine design. 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.

The majority of exercise-induced hypertrophy subsequent to traditional resistance training programs results from an increase of sarcomeres and myofibrils added in parallel. 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 cross-sectional area.


Muscle tissue does not undergo significant cell replacement throughout life. An efficient method for cell repair is therefore required to maintain skeletal mass. This is carried out through the dynamic balance between muscle protein synthesis and degradation.

Muscle hypertrophy occurs when protein synthesis exceeds protein breakdown. Hypertrophy is thought to be mediated by the activity of satellite cells, these ‘‘myogenic stem cells’’ are normally quiescent but become active when a sufficient mechanical stimulus is imposed on skeletal muscle.

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.

Moreover, satellite cells coexpress various myogenic regulatory factors (including Myf5, MyoD, myogenin, and MRF4) that aid in muscle repair, regeneration, and growth. These regulatory factors bind to sequence specific DNA elements present in the muscle gene promoter, with each playing distinct roles in myogenesis.


MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins known as myogenic regulatory factors (MRFs). These bHLH (basic helix loop helix) transcription factors act sequentially in myogenic differentiation. Vertebrate MRF family members include MyoD1, Myf5, myogenin, and MRF4 (Myf6). In non-vertebrate animals, a single MyoD protein is typically found.

MyoD is one of the earliest markers of myogenic commitment. MyoD is expressed at extremely low and essentially undetectable levels in quiescent satellite cells, but expression of MyoD is activated in response to exercise or muscle tissue damage. The effect of MyoD on satellite cells is dose-dependent; high MyoD expression represses cell renewal, promotes terminal differentiation and can induce apoptosis. Although MyoD marks myoblast commitment, muscle development is not dramatically ablated in mouse mutants lacking the MyoD gene. This is likely due to functional redundancy from Myf5 and/or Mrf4. Nevertheless, the combination of MyoD and Myf5 is vital to the success of myogenesis.


The function of MyoD in development is to commit mesoderm cells to a skeletal myoblast lineage, and then to regulate that continued state. MyoD may also regulate muscle repair. MyoD mRNA levels are also reported to be elevated in aging skeletal muscle. One of the main actions of MyoD is to remove cells from the cell cycle (halt proliferation for terminal cell cycle arrest in differentiated myocytes) by enhancing the transcription of p21 and myogenin.

MyoD is inhibited by cyclin dependent kinases (CDKs). CDKs are in turn inhibited by p21. Thus MyoD enhances its own activity in the cell in a feedforward manner. Sustained MyoD expression is necessary for retaining the expression of muscle-related genes. MyoD is also an important effector for the fast-twitch muscle fiber (types IIA, IIX, and IIB) phenotype.

Coactivators and repressors

IFRD1 is a positive cofactor of MyoD, as it cooperates with MyoD at inducing the transcriptional activity of MEF2C (by displacing HDAC4 from MEF2C); moreover IFRD1 also represses the transcriptional activity of NF-κB, which is known to inhibit MyoD mRNA accumulation.

NFATc1 is a transcription factor that regulates composition of fiber type and the fast-to-slow twitch transition resulting from aerobic exercise requires the expression of NFATc1. MyoD expression is a key transcription factor in fast twitch fibers which is inhibited by NFATc1 in oxidative fiber types.

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