Regeneration of Muscle

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.

Keywords: regeneration; necrosis; inflammation; myogenesis; muscle satellite cells

Figure 1.

Drawing of a portion of a skeletal muscle fibre, showing the relationship between a myonucleus and a satellite cell.

Figure 2.

Drawings taken from actual electron micrographs, showing the major stages in the degeneration and regeneration of a mammalian skeletal muscle fibre. (a) Original muscle fibre, which has been damaged irreversibly by ischaemia. (b) The cellular phase of muscle fibre degeneration. Macrophages (M) have invaded the degenerating muscle fibre and have removed most of the degenerating cytoplasm. Just beneath the basal lamina (arrow), which surrounds the entire original muscle fibre, activated satellite cells, now called myoblasts (Mb), line up in preparation to fuse and form new muscle fibres within the original basal lamina. (c) Section through a regenerating myotube, showing a row of central nuclei and bundles of contractile material located at the periphery of the myotube. (d) Mature regenerated muscle fibre, showing a structure very similar to that of a normal muscle fibre.

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Further Reading

Grounds MD and Relaix F (2009) Myogenic precursor cells. In: Hilton‐Jones D, Griggs RC, Bushby K and Karpati G (eds) Disorders of Voluntary Muscles Section I – Scientific Basis of Muscle Disease, 8th edn, pp. 20–36. http://www.cherylluzet.co.uk/sitefiles/Index.htm. Cambridge: Cambridge University Press.

Grounds MD and Yablonka‐Reuveni Z (1993) Molecular and cell biology of skeletal muscle regeneration. In: Partridge TA (ed.) Molecular and Cell Biology of Muscular Dystrophy, pp. 210–256. London: Chapman and Hall.

Lynch GS (ed.) (2011) Sarcopenia for Advances in Experimental Medicine and Biology Series chap. 25. The Netherlands: Springer.

Schiaffino S and Partridge TA (eds) (2008) Skeletal Muscle Repair and Regeneration chap. 25. The Netherlands: Springer.

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Grounds, Miranda D(Aug 2011) Regeneration of Muscle. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001106.pub2]