Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models

Muscle wasting occurs in a variety of conditions, such as cancer cachexia, diabetes, renal failure and heart failure, and aging itself. The survival and quality of life of these patients and of the older person can be improved by counteracting loss of muscle mass and strength, and different approaches to this have been explored, including nutritional supplementation, resistance training and anabolic drugs. Recent advances in understanding the mechanisms responsible for muscle atrophy may pave the way to new and perhaps more effective treatments.During the past several years, experimental studies based on rigorous genetic approaches have started to dissect the signaling pathways involved in muscle-mass regulation. Although studies on cultured muscle cells have contributed to identify these pathways, definitive evidence of their physiological relevance can only be obtained using in vivo systems, when myofibers have a mature structure, and the integrity of the neuromuscular and musculoskeletal system is preserved.Two in vivo genetic approaches have been used to understand how muscle mass is regulated. One is based on the generation of transgenic and knockout mice, in which expression of muscle regulatory genes is selectively modified. The potential of the traditional gene overexpression or deletion approaches has been fully exploited with the introduction of the Cre/loxP technique and the use of inducible transgenes, which allows for the modulation of gene expression specifically in muscle tissues and at different developmental stages. It is thus possible to distinguish between the effects on the regulation of muscle growth during development from the effects on the maintenance of muscle mass in adulthood. An alternative approach to address muscle-mass regulation in the adult is based on in vivo transfection of skeletal muscles by electroporation with plasmids coding for specific components of signaling pathways, or for mutants bearing constitutively active or dominant