The role of systemic inflammation in age-related muscle weakness and wasting.

Ageing is associated with a slow, but progressive muscle weakness, which is largely attributable to muscle wasting. A diminished function of satellite cells at old age may hamper preservation and repair from (contraction)-induced injury and contribute to the age-related muscle wasting. Satellite cell function may be affected by circulating factors, as muscle regeneration in old mice sharing the circulation of young mice is not impaired. Chronic low-grade systemic inflammation in old organisms may be that environmental factor. Indeed, the inflammatory cytokine tumor necrosis factor-alpha (TNFalpha) negatively affects the muscle regenerating capacity. TNFalpha destabilizes MyoD, a muscle-specific transcription factor involved in satellite cell proliferation and differentiation, and induces apoptosis of satellite cells, particularly at old age. Here it is proposed that some of these effects are mediated by TNFalpha-induced expression of inhibitors of differentiation proteins. Yet, the increase in TNFalpha during the normal inflammatory response helps, rather than impairs, the repair process. This apparent contradiction may be resolved by the fact that the effects of TNFalpha are concentration and time dependent. Thus, the negative effect of systemic inflammation on muscle strength at old age may only become apparent when it exceeds a certain threshold and persists for a prolonged period.