The need to more precisely define aspects of skeletal muscle regeneration

• The term ‘muscle regeneration’ should be precisely defined to avoid confusion.
• Myofibre necrosis is required for regeneration of post-natal skeletal muscles that results in new muscle formation (and ideally full maturation of these myofibres).
• The term ‘muscle regeneration’ should not be used for repair of damage to sarcomere structure or the extracellular matrix of muscle tissue.
• Restoration of muscle mass by hypertrophy, after myofibreatrophy, does not involve ‘regeneration’.
• Many markers of regenerated muscles, e.g. central myonuclei, expression of embryonic/neonatal myosins ormyogenin, myofibre branching/splitting, or satellite cell activation/proliferation(often without fusion), can also occur in other situations (such as denervation) so care must be taken in interpretation of such features in biopsied or ageing muscles.

A more precise definition of the term ‘skeletal muscle regeneration’ is required to reduce confusion and misconceptions. In this paper the term is used only for events that follow myofibre necrosis, to result in myogenesis and new muscle formation: other key events include early inflammation and revascularisation, and later fibrosis and re-innervation. The term ‘muscle regeneration’ is sometimes used casually for situations that do not involve myonecrosis; such as restoration of muscle mass by hypertrophy after atrophy, and other forms of damage to muscle tissue components. These situations are excluded from the definition in this paper which is focussed on mammalian muscles with the long-term aim of clinical translation to enhance new muscle formation after acute or chronic injury or during surgery to replace whole muscles. The paper briefly outlines the cellular events involved in myogenesis during development and post-natal muscle growth, discusses the role of satellite cells in mature normal muscles, and the likely incidence of myofibre necrosis/regeneration in healthy ageing mammals (even when subjected to exercise). The importance of the various components of regeneration is outlined to emphasise that problems in each of these aspects can influence overall new muscle formation; thus care is needed for correct interpretation of altered kinetics. Various markers used to identify regenerating myofibres are critically discussed and, since these can all occur in other conditions, caution is required for accurate interpretation of these cellular events. Finally, clinical situations are outlined where there is a need to enhance skeletal muscle regeneration: these include acute and chronic injuries or transplantation with bioengineering to form new muscles, therapeutic approaches to muscular dystrophies, and comment on proposed stem cell therapies to reduce age-related loss of muscle mass and function. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation.