Cellular Dynamics of Skeletal Muscle Regeneration

Abstract

The function of many organs, including skeletal muscle, depends on its three-dimensional structure. Muscle regeneration therefore requires not only reestablishment of myofibers, but restoration of tissue architecture. Resident muscle stem cells (SCs) are essential for regeneration, but how SCs regenerate muscle architecture is largely unknown. We address this problem using genetic labeling of SCs and whole mount imaging to reconstruct in three dimensions muscle regeneration. Unexpectedly, we found that the residual basement membrane of necrotic myofibers is critical for promoting fusion and orienting regenerated myofibers and myofibers form via two distinct phases of fusion. Furthermore, the centralized myonuclei characteristic of regenerated myofibers are associated with myofibrillogenesis and permanently mark regenerated myofibers. Finally, we elucidate a new cellular mechanism for the formation of branched myofibers, a pathology characteristic of diseased muscle. We provide a new synthesis of the cellular events of regeneration and show these differ from those used during development.