Regenerative function of immune system: Modulation of muscle stem cells

• Immune cells infiltrate damaged skeletal muscles to release cytokines, chemokines and growth factors into the localised area that alter the micro-environment to clear cellular debris and activate muscle stem cells.
• In young adults, the factors released by T-cells, in particular the regulatory T-cells, can extend the period of satellite cell proliferation to enhance muscle repair.
• In old adults, the T-cells do not release appropriate factors into the micro-environment and this may contribute to inadequate muscle recovery and consequently, to age-related deficits in muscle size and function.
• Identification of the factors released by young immune cells to regulate muscle regeneration could lead to the development of novel therapeutic agents to treat muscle wasting disorders and ageing.

Ageing is characterised by progressive deterioration of physiological systems and the loss of skeletal muscle mass is one of the most recognisable, leading to muscle weakness and mobility impairments. This review highlights interactions between the immune system and skeletal muscle stem cells (widely termed satellite cells or myoblasts) to influence satellite cell behaviour during muscle regeneration after injury, and outlines deficits associated with ageing. Resident neutrophils and macrophages in skeletal muscle become activated when muscle fibres are damaged via stimuli (e.g. contusions, strains, avulsions, hyperextensions, ruptures) and release high concentrations of cytokines, chemokines and growth factors into the microenvironment. These localised responses serve to attract additional immune cells which can reach in excess of 1 × 105 immune cell/mm3 of skeletal muscle in order to orchestrate the repair process. T-cells have a delayed response, reaching peak activation roughly 4 days after the initial damage. The cytokines and growth factors released by activated T-cells play a key role in muscle satellite cell proliferation and migration, although the precise mechanisms of these interactions remain unclear. T-cells in older people display limited ability to activate satellite cell proliferation and migration which is likely to contribute to insufficient muscle repair and, consequently, muscle wasting and weakness. If the factors released by T-cells to activate satellite cells can be identified, it may be possible to develop therapeutic agents to enhance muscle regeneration and reduce the impact of muscle wasting during ageing and disease.