Key concepts in muscle regeneration: muscle “cellular ecology” integrates a gestalt of cellular cross-talk, motility, and activity to remodel structure and restore function

Abstract

This review identifies some key concepts of muscle regeneration, viewed from perspectives of classical and modern research. Early insights noted the pattern and sequence of regeneration across species was similar, regardless of the type of injury, and differed from epimorphic limb regeneration. While potential benefits of exercise for tissue repair was debated, regeneration was not presumed to deliver functional restoration, especially after ischemia–reperfusion injury; muscle could develop fibrosis and ectopic bone and fat. Standard protocols and tools were identified as necessary for tracking injury and outcomes. Current concepts vastly extend early insights. Myogenic regeneration occurs within the environment of muscle tissue. Intercellular cross-talk generates an interactive system of cellular networks that with the extracellular matrix and local, regional, and systemic influences, forms the larger gestalt of the satellite cell niche. Regenerative potential and adaptive plasticity are overlain by epigenetically regionalized responsiveness and contributions by myogenic, endothelial, and fibroadipogenic progenitors and inflammatory and metabolic processes. Muscle architecture is a living portrait of functional regulatory hierarchies, while cellular dynamics, physical activity, and muscle–tendon–bone biomechanics arbitrate regeneration. The scope of ongoing research—from molecules and exosomes to morphology and physiology—reveals compelling new concepts in muscle regeneration that will guide future discoveries for use in application to fitness, rehabilitation, and disease prevention and treatment.

Angiogenesis precedes myogenesis during regeneration following biopsy injury in skeletal muscle

“…These experiments are the first to illustrate that revascularization precedes the replacement of myofibers in adult skeletal muscle following injury. Our findings are consistent with the interpretation that establishing a vascular supply in the provisional matrix generates conditions that support the regeneration of myofibers (6). The outcome of this study contrasts with injuries in which the basal laminae (and progenitor cells) persist and angiogenesis occurs concomitant with myogenesis (9, 13, 47).…”

“…Crosstalk between surviving SCs and ECs occurs under the influence of immune cells and FAPs (3, 6, 9–13, 20, 40, 41). FAPs are identified by the expression of mesenchymal stem cell surface proteins (e.g., Sca-1, CD34, PDGFRα) and reside in the interstitial space adjacent to the microvasculature (21, 22, 42).…”

“…FAPs are identified by the expression of mesenchymal stem cell surface proteins (e.g., Sca-1, CD34, PDGFRα) and reside in the interstitial space adjacent to the microvasculature (21, 22, 42). Upon injury, FAPs enter the cell cycle to proliferate, localize to the site of tissue damage, differentiate into fibroblasts and adipocytes [but not into SCs or myofibers (20, 22, 40)], and work in concert with macrophages and ECs to promote myofiber regeneration (6, 22, 41, 43). Our finding that CD45 + and PDGFRα + cells invade the provisional matrix within 1 dpi following punch biopsy (Fig.…”

A pilot study on nitration/dysfunction of NK1 segment of myogenic stem cell activator HGF

“…Skeletal muscle is particularly susceptible to the effects of peroxynitrite as it is an organ that continuously generates reactive oxygen and nitrogen species, even under physiological conditions and definitely heightens their generation in pathologic disorders [ [14] , [15] , [16] , [17] , [18] ]. Skeletal muscles display a high regenerative capacity that depends on sequential dynamics of myogenic stem satellite cells, which are normally quiescent or dormant and respond to activation signals to enter the cell cycle [ [19] , [20] , [21] ] in a NO-radical-hepatocyte growth factor (HGF)-dependent manner [ [22] , [23] , [24] , [25] , [26] ]. The regenerative function of satellite cells is orchestrated by their interaction with a complex of regulatory microenvironmental factors to adapt skeletal muscle function to physiological demand and metabolic changes [ 27 , 28 ].…”

The Therapeutic Potential of Exosomes in Soft Tissue Repair and Regeneration

“…During skeletal muscle repair, activated satellite cells differentiate into myoblasts. Then, these myoblasts undergo terminal differentiation, and eventually form multinucleated myotubes [ 118 , 119 ].…”