Articles Nutrition/Training Satellite Cells, Myonuclear Domains, And a la Carte Regulatory Factors for Muscle Growth-- Part 1
Myofiber size is dynamically regulated, increasing, and decreasing depending on muscle use. Hypertrophy is defined by increases in myofiber cross-sectional area and mass, as well as myofibrillar protein content. During muscle growth, cell surface receptors, relay signals from extracellular growth factors, hormones, and cytokines through cell surface receptors into the interior of the myofiber. These signals are then distilled through a myriad of signaling pathways to regulatory compartments known as nuclei within the myofiber. Therein, "myonuclei" harness growth factor-induced signaling into transcriptional signatures, protein synthesis, and notably, muscle growth. Myofibers contain many hundreds of nuclei each of which has a nuclear domain (explained below).
What are "Satellite cells" that the eminent Dr Connelly referred to?
Myofibers are surrounded by a basal lamina; this acts as a protective sheath, and structural scaffold during muscle repair. Importantly, myofibers are enriched with a population of formidable stem cells; these lie "satellite" or outside the parent myofiber, but beneath the surrounding basal lamina. Thus satellite cells are defined anatomically. In addition, satellite cells are defined functionally; in response to injury, satellite cells proliferate and their progeny myoblasts migrate to sites of damage. Therein, myoblasts fuse with each other to form nascent myofibers or with existing myofibers, to restore muscle architecture. This process of satellite cell myogenesis is essential for postnatal growth, muscle growth, muscle regeneration after injury and muscle growth after atrophy. In this manner, satellite cells are indispensable for muscle growth.
What does Dr Connelly mean by differentiation?
Interestingly, myofibers are specialized for multiple tasks including contraction, locomotion, postural support, and breathing. Abiding to universal biologic principles, specialization (also known as differentiation), is accompanied by a loss of "stemness." Toward this end, myogenic stem cells that perpetuatue muscle growth undergo a process of differentiation; activation of a myogenic transcriptional program and suppression of nonmuscle genes. A distinct and temporal pattern of muscle -specific gene expression including Myf5, MyoD, myogenin, and myosin heavy chain synthesis occurs in satellite cells. Although this process is essential for muscle function, myonuclei lose the capacity to replicate and restore fmuscle architecture in an injured myofiber.
As these myonuclei have irrevocably exited the cell cycle, the repair and growth of skeletal muscle is dependent on a local source of myogenic stem cells. There is biochemical, genetic and pharmacologic evidence illustrating that satellite cells are indispensable for muscle growth and repair after injury.
What does Dr Connelly mean by "myonuclear domain?"
The initial phase of myofiber hypertrophy is characterized by enhanced transcription and translation leading to enhanced protein accretion in the area surrounding a myonucelus. A nuclear domain is the volume of cytoplasm within the myofiber regulated by the gene products of a single myonucleus. Skeletal muscle hypertrophy is accompanied by proportional increases in both myofiber volume and myonuclei such that the ratio of myonuclei /cytoplasm, or nuclear domain, remains relatively constant. As myonuclei are terminally differentiated, myonuclear addition during skeletal muscle hypertrophy is dependent upon activation of local satellite cells. Importantly, fusion of satellite cells with growing myofibers re-establishes the endogenous ratio of DNA/cytoplasmic volume. Thus, small increments in myofiber cross-sectional area and cytoplasmic volume can be supported by increased transcriptional and translational activity of myonuclei but a threshold or "myonuclear domain ceiling" exists such that further increases in myofiber cross-sectional area require satellite cell-dependent myonuclear addition.
Growth factor-induced regeneration
Muscle damage following injury is characterized by a loss in plasma membrane integrity, release of intracellular constituents and myofiber degradation. Partial or complete myofiber degradation can occur depending on the magnitude of injury. The diffusion of growth factors into the extracellular environment establishes a chemotactic gradient for both immune cells and satellite cells. In part two, I will elaborate on the role of individual growth factors in muscle regeneration after injury.
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