The question of why muscles grow after exercise seems to have a simple answer - they grow by repairing themselves from the damage exercise causes. However, this theory does not explain the loss of muscle mass that occurs after long periods of rest or in microgravity environments such as those encountered in space. Authors of a new report suggest that muscle growth is regulated by structures within muscle cells that sense changes in mechanical force.

Muscle fibers lengthen and shorten in cycles to create muscle movement. Fast muscle fiber cycling is utilized during the fight or flight response, generating nearly instantaneous motion. Over periods of several days, muscles regulate their growth based on the number of these contraction cycles. But how muscles “know” how much they have been used has yet to be elucidated.

The sarcomere is the smallest structural unit of striated muscle (i.e., skeletal and cardiac muscle) and is composed of thin actin and thick myosin filaments, which slide against each other to create the force needed for contraction and relaxation. Titin is a protein at the core of the myosin filaments that changes shape when force is applied. Force “opens” the titin protein structure, exposing a molecular site for phosphorylation (i.e., adding a phosphate group). This phosphorylation initiates a signaling cascade that results in changes to gene expression that affect long-term growth and atrophy of skeletal muscles.

The authors created a mathematical model to explain the mechanism of the mechanosensing function of titin. The model was divided into three parts. The first part of the model characterized the opening of the titin protein structure in response to force. The second part of the model characterized the creation and degradation of signaling molecules that are downstream in the signaling cascade initiated by titin phosphorylation. The third part of the model characterized how muscle cells compensate for the depletion of short-term adenosine triphosphate (ATP) energy stores that results from energy production through oxidative phosphorylation.

From the modeling calculations, the authors found that titin acts as a mechanosensitive switch that is put under extreme force during resistance exercise (e.g., weight lifting) and less force during endurance exercise (e.g., jogging). The model also explained that titin phosphorylation geometrically inhibits the function of ribosomes, the cell structures that build proteins. Following exercise, some protein synthesis in the muscle is inhibited; however, after a lag of days or weeks, repeated exercise increases the rate of ribosome gene expression and synthesis. Building on this information, the model yielded that these alterations in protein synthesis are ultimately responsible for muscle hypertrophy following exercise and muscle atrophy following extended rest.

The authors noted that this important research may identify targets for future therapies that prevent the loss of muscle mass that occurs with age and with diseases such as cancer and HIV.

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