Insights into the Roles of Aging and Chemokine Signaling During Neuromuscular Regeneration

Abstract

Aging is associated with delayed skeletal muscle recovery from injury leading to increased morbidity in the elderly population. Inefficiency of aged muscle regenerative capacity is primarily attributed to the decline in numbers and functionality of the muscle stem cells (MuSCs) with aging. The identification of abnormalities in the aged regenerative environment which impair MuSCs regenerative capacity, and targeting them to develop therapeutic strategies has become a focus of the field. Various studies have observed that myofiber degeneration after injury was associated with loss of innervation. However, whether age-related differences exist in the rate or extent of reinnervation has not been explored. Here we identify a novel anomaly in the aged regenerating environment, where aged regenerating muscle show more extensive and prolonged denervation. Consistent with the crucial role of neuromuscular junction (NMJ) integrity in proper myofiber regeneration, we find that denervated regenerating myofibers in aged muscle are smaller in diameter than innervated myofibers. On the other hand, our lab has recently identified persistent elevated expression of C-C chemokine receptor type 2 (Ccr2) ligands in aged regenerating muscle and that timely pharmacologic inhibition of Ccr2 signaling significantly improves aged muscle regeneration. Moreover, our lab discovers MuSC-derived progenitor (MP) expression of Ccr2 and the inhibitory effect of Ccr2 signaling on MP differentiation and fusion. Here we develop and characterize a MuSC-targeted conditional Ccr2 knockout mouse to prospectively utilize to examine the role of Ccr2 signaling in MPs during various stages of aged muscle regeneration. Collectively our work sheds the light on MuSC Ccr2 signaling and myofiber denervation as causative factors in aged regenerative impairment which may become future therapeutic targets to improve aged muscle regeneration.