Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function

Abstract

During the aging process, mammals lose up to a third of their skeletal muscle mass and strength. Although the mechanisms underlying this loss are not entirely understood, we attempted to moderate the loss by increasing the regenerative capacity of muscle. This involved the injection of a recombinant adeno-associated virus directing overexpression of insulin-like growth factor I (IGF-I) in differentiated muscle fibers. We demonstrate that the IGF-I expression promotes an average increase of 15% in muscle mass and a 14% increase in strength in young adult mice, and remarkably, prevents aging-related muscle changes in old adult mice, resulting in a 27% increase in strength as compared with uninjected old muscles. Muscle mass and fiber type distributions were maintained at levels similar to those in young adults. We propose that these effects are primarily due to stimulation of muscle regeneration via the activation of satellite cells by IGF-I. This supports the hypothesis that the primary cause of aging-related impairment of muscle function is a cumulative failure to repair damage sustained during muscle utilization. Our results suggest that gene transfer of IGF-I into muscle could form the basis of a human gene therapy for preventing the loss of muscle function associated with aging and may be of benefit in diseases where the rate of damage to skeletal muscle is accelerated.

Insulin and Wnt1 Pathways Cooperate to Induce Reserve Cell Activation in Differentiation and Myotube Hypertrophy

“…In agreement with previous reports suggesting that insulin/IGF-1 promotes proliferation, we observed 5-bromo-2-deoxyuridine incorporation into mononucleated reserve cells upon treatment of differentiated C2 cells with insulin or insulin and LiCl (unpublished observations). In vivo, the hypertrophic effect of IGF-1 alone on skeletal muscles in mice is well documented (Barton-Davis et al, 1998;Musaro et al, 2001). A similar effect was shown on myotube hypertrophy ex vivo (Rommel et al, 2001).…”

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…Such properties of IGF-1 have been shown to be beneficial to ageing, atrophic, and dystrophic muscles (Barton-Davis et al, 1998;Lynch et al, 2001;Musarò et al, 2001). IGF-1 has the additional effect of converting fibres to a fast glycolytic phenotype, as evident by raised expression of glycolytic enzymes in IGF-1-transfected C2C12 myotubes (Semsarian et al, 1999), by modest rise in fast 2b fibres in transgenic mice carrying muscle IGF-1 isoform driven by a rat myosin light chain (MLC)-1/3 promoter (Musarò et al, 2001) and by raised type 2a and 2b fibres at the expense of slow fibres in IGF-1-treated dystrophic mice (Lynch et al, 2001).…”

Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury

“…[15][16][17] Viral-mediated IGF-I delivery prevents the age-related loss of skeletal muscle function and has been shown to promote skeletal muscle hypertrophy in an additive manner when combined with resistance exercise training. 18,19 Non-viral plasmid-based electroporationassisted IGF-I gene transfer has been shown to enhance skeletal muscle regeneration after laceration injury. 20 Administration of recombinant IGF-I protein has been shown to promote restoration of muscle function after strain or laceration injuries.…”