© 2002 Kluwer Academic Publishers. Printed in the Netherlands. 19 Reasons for the degeneration of ageing skeletal muscle: a central role for IGF-1 signalling ∗

This paper examines two major possibilities for the striking loss of skeletal muscle mass and strength that occurs in very old animals and humans. It is concluded that muscle regeneration is not significantly impaired with age. Instead, it seems that individual myofibres undergo atrophy, with selective death of the fast type 2B myofibres, due to the combined effects of many age-related changes the main causes being: nutrition (under-nutrition and lack of vitamin D), decreased hormone levels (e.g growth hormone, testosterone), reduced physical activity, and a loss of nerves that innervate the muscles. The discussion focusses on the central role of a local muscle form of insulin-like growth factor-I (IGF-I) in muscle hypertrophy, atrophy and motorneurone loss. Reduced IGF-I signalling is involved in muscle atrophy and results from decreased muscle exercise, reduced growth hormone and insulin levels, reduced vitamin D, and treatment with drugs like corticosteroids, dexamethasone, and cyclosporin. In addition, elevated levels of inflammatory cytokines like TNF-α and IL-6 can cause muscle wasting (cachexia) although this is usually associated with disease, and TNF-α may also act (at least in part) by inhibiting IGF-I signalling. The possible clinical prevention of age-related muscle wasting (and associated motorneurone loss) by the locally acting muscle isoform of IGF-I is discussed