Muscle damage following resistance exercise is characterized by a loss in plasma membrane integrity, release of intracellular constituents, and myofiber degradation. As described by Dr Connelly in his interview with Heavy Muscle Radio, a localized source of functionally-competent stem cells called satellite cells, restore myofiber formation and muscle architecture through a highly-regulated process. Toward this end, growth factors released from injured fibers, connective tissue, and infiltrating immune cells engage a diverse array of receptors located at the surface of satellite cells. This process promotes an ordered process of satellite cell activation (release from a quiescent state), migration to sites of damage, and fusion with each other to form new myofibers. As the ratio of myonuclei/sarcoplasmic volume is fixed, this process of satellite cell fusion re-establishes the myonuclear domain in growing myofibers.
Regulatory factors central to Satellite Cell Activation
Dr Connelly referred to a complex of proteins, located beneath the surface of the sarcolemma, that are important for satellite cell dynamics and muscle function. On this basis, the cytoskeletal protein dystrophin, is part of a protein assembly that maintains myofiber integrity during mechanical stress. Additionally, proteins called focal adhesion kinases, transduce mechanical stimuli (stretch, contraction etc.) at the surface of the myofiber, to the myonuclei distributed throughout the sarcoplasm. This signal transduction process activates a specific pattern of gene expression; a blueprint for muscle growth. Interestingly, an enzyme that synthesizes nitric oxide is also located within these protein complexes beneath the myofiber surface. This enzyme responsible for skeletal muscle nitric oxide synthesis is distinct from its endothelial counterpart. Endothelial cell-derived nitric oxide is a vasodilatory mediator in the circulatory system. In contrast, when released from skeletal myofibers, nitric oxide regulates myofiber formation during muscle repair.
Nitric oxide maintains satellite cell quiescence and triggers satellite cell activation
To describe this paradox of specificity, eminent work in this field of physiology explains the binary function of nitric oxide exquisitely. The underlying tenet is that uninjured myofibers release nitric oxide in a pulsatile manner. This ordered pattern of release, signals to the satellite cells nearby to remain in a quiescent, inactive state. Conversely, mechanical shear stress associated with repeated muscular contraction elicits a continuous release of nitric oxide from the interior of the myofiber. This unremitting flow of nitric oxide activates a cascade of events responsible for satellite cell activation. Moreover, during eccentric contractions, stretch, or injury, the integrity of the myofiber membrane is compromised. Intuitively, perforations/tears in the myofiber membrane allow a continuous release of nitric oxide that is essential for muscle growth.
To extend these findings, a series of studies were performed to elucidate the mechanistic role of nitric oxide in satellite cell activation and muscle growth. Of note, the extracellular matrix/connective tissue surrounding the myofiber is enriched with growth factors. Toward this end, mechanical stimuli trigger growth factor release from myofibers into the extracellular milieu. In addition, infiltrating immune cells secrete regulatory factors important for satellite cell dynamics. Importantly, growth factors often require enzymatic cleavage. The prevailing theory for nitric oxide as a regulatory factor in satellite cell biology describes a model in which nitric oxide activates a set of enzymes collectively known as matrix metalloproteinases (MMP's). MMP's transform extracellular growth factors into their active form. Acting as ligands for receptors on the surface of satellite cells, growth factors trigger intracellular kinase pathways leading to a pattern of muscle-specific gene induction. This ordered process directs satellite cell activation, proliferation, and differentiation; cellular responses essential for myofiber formation during muscle growth.
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