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Molecular mechanisms of increased protein synthesis

This is an excerpt from Physiology of Sport and Exercise 8th Edition With HKPropel Access by W. Larry Kenney,Jack H. Wilmore & David L. Costill.

Like all adaptations to chronic exercise, the muscle hypertrophy that results from appropriate resistance training relies on an increase in the production of specific proteins in response to stress-related stimuli on the muscle. The stress of repeated bouts of exercise activates signaling pathways in the muscle fibers that, in turn, switch on specific genes to synthesize the new proteins. Although this general mechanism is true whether the training is endurance exercise or resistance exercise, the second messenger signaling pathways and transcriptional activators through which resistance exercise leads to protein synthesis and hypertrophy are specific to that form of exercise.

The primary signal for increased protein synthesis is the repeated mechanical stretch on the muscle that occurs during resistance exercise (i.e., the force applied to the muscle fibers).4 Figure 11.7 shows the intracellular signaling molecules involved. The repeated stretch on muscle fibers leads to the increased synthesis of the signaling molecule insulin-like growth factor 1 (IGF-1). Experiments that have infused IGF-1 or overexpressed it genetically have induced significant muscle hypertrophy in animal models.4 Increased IGF-1 then leads to activation of another important signaling protein, protein kinase B (also known as Akt). Akt stimulates production of the signaling molecule mTOR4 (mechanistic target of rapamycin), an enzyme or kinase.

Figure 11.7 The stimulus (mechanical stretch) and signaling pathway through which resistance training leads to muscle hypertrophy.
Figure 11.7 The stimulus (mechanical stretch) and signaling pathway through which resistance training leads to muscle hypertrophy.

The rate of protein synthesis within the myofibrils is controlled primarily by mTOR.4 It integrates the input from upstream pathways, including insulin and growth factors and amino acids (see figure 11.8), and controls transcription of messenger RNA (mRNA). If mTOR is blocked experimentally, resistance exercise does not result in muscle hypertrophy. Among its other important functions, mTOR senses cellular nutrient and oxygen levels, so it is also activated by the proper timing of protein intake, specifically proteins rich in leucine. So, delivering leucine to muscles during the window of opportunity will increase mTOR more than acute exercise alone and lead to enhanced protein synthesis and muscle hypertrophy.

The increased protein synthesis with enhanced dietary amino acid availability occurs not only because of the greater net supply of amino acids but also because of changes in hormonal concentrations that create a more favorable anabolic environment. Insulin serves as a strong anabolic stimulus for skeletal muscle hypertrophy, as shown in figure 11.8. In the presence of adequate substrate, insulin (which rises after a meal) is capable of stimulating skeletal muscle protein synthesis and hypertrophy in young muscles.

Insulin stimulates protein synthesis from available amino acids by promoting a more efficient conversion of genetic codes carried by mRNA into proteins, a process known as translation. This process is accomplished by cellular organelles known as ribosomes, so it stands to reason that increasing ribosome content in the muscle fibers (i.e., increasing the translational capacity) will also result in more protein being synthesized. Ribosome biogenesis, the creation of new ribosomes, appears to be an important mechanism regulating muscle size in response to resistance exercise. In fact, when the synthesis of new ribosomes is blocked biochemically, muscles fail to undergo hypertrophy. Notably, recent studies show that mTOR is involved in the synthesis of ribosomes in the cell nucleus in addition to its role in regulating translation in the cytoplasm (see figure 11.8), which puts this kinase at center stage in the muscle growth process.

Figure 11.8 Schematic representation of the separate and combined roles of resistance training, insulin, and amino acid intake on skeletal muscle protein synthesis. Redrawn from Dickinson, Volpi, and Rasmussen (2013).5
Figure 11.8 Schematic representation of the separate and combined roles of resistance training, insulin, and amino acid intake on skeletal muscle protein synthesis.
Redrawn from Dickinson, Volpi, and Rasmussen (2013).5