Regeneration of Muscle

Abstract

Abstract Muscle regeneration is the process by which damaged skeletal, smooth or cardiac muscle undergoes biological repair and formation of new muscle in response to death (necrosis) of muscle cells. The success of the regenerative process depends upon the extent of the initial damage and many intrinsic and environmental factors. Key cellular events required for regeneration include inflammation, revascularisation and innervation, in addition to myogenesis where new muscle is formed. In mammals, new muscle formation is generally excellent for skeletal muscle but poor for cardiac muscle; however a greater capacity for regeneration of cardiac muscle is seen in fish and some anurans. These aspects of regeneration are discussed with respect to myogenic stem cells, molecular regulation, ageing and implications for human therapies, with a strong focus on skeletal muscle. Other situations of muscle damage and restoration that do not involve necrosis (e.g. sarcomere disruption and atrophy) are here not considered as regeneration. Key Concepts: Necrosis is required for muscle regeneration. Inflammation is essential to remove necrotic tissue and initiate myogenesis. New blood vessel formation is required after major injury of muscles. Skeletal muscle has an excellent capacity for regeneration. The major source of myogenic precursor (stem) cells is still considered to be the satellite cell, although other cells lying outside the myofibre may contribute to myogenesis. The source of the myogenic precursor cells (myoblasts) varies between conventional tissue regeneration and epimorphic regeneration (where mature cells dedifferentiate). The microenvironment, including the extracellular matrix, affects all aspects of regeneration, for example, the muscle precursors and their capacity for new muscle formation (and fibrosis impairs myogenesis). Reinnervation is essential for functional recovery of skeletal muscle. Excellent myogenesis can occur in geriatric muscle, although systemic factors essential for regeneration, for example, inflammation and innervation, may be suboptimal. Mammalian heart muscle has a very poor capacity for regeneration and severe damage (e.g. heart attack) results in fibrosis and impaired function. In contrast, the hearts of vertebrates such as salamanders and zebrafish can regenerate; the new heart muscle is derived from the dedifferentiation and proliferation of mature cardiomyocytes. It is hoped that an understanding of mechanisms involved in these situations will present opportunities to induce regeneration of damaged human cardiac muscle.