Regulation of muscle atrophy in aging and disease.
Muscle aging is characterized by a decline in functional performance and restriction of adaptability, due to progressive loss of muscle tissue coupled with a decrease in strength and force output. Together with selective activation ofapoptotic pathways, a hallmark of age-related muscle loss or sarcopenia is the progressive incapacity of regeneration machinery to replace damaged muscle. These characteristics are shared by pathologies involving muscle wasting, such as muscular dystrophies or amyotrophic lateral sclerosis, cancer and AIDS, all characterized by alterations in metabolic and physiological parameters, progressive weakness in specific muscle groups. Modulation ofextracellular agonists, receptors, protein kinases, intermediate molecules, transcription factors and tissue-specific gene expression collectively compromise the functionality of skeletal muscle tissue, leading to muscle degeneration and persistent protein degradation through activation ofproteolytic systems, such as calpain, ubiquitin-proteasome and caspase. Additional decrements in muscle growth factors compromise skeletal muscle growth, differentiation, survival and regeneration. A better understanding of the mechanisms underlying the pathogenesis of muscle atrophy and wasting associated with different diseases has been the objective of numerous studies and represents an important first step for the development of therapeutic approaches. Among these, insulin-like growth factor-1 (IGF-1) has emerged as a growth factor with a remarkably wide range of actions and a tremendous potential as a therapeutic in attenuating the atrophy and frailty associated with muscle aging and diseases. In this chapter we provide an overview of current concepts in muscle atrophy, focusing specifically on the molecular basis of IGF-1 action and survey current gene and cell therapeutic approaches to rescue muscle atrophy in aging and disease.
Vinciguerra
Manlio
M
Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini, 32, 00015 Monterotondo (Rome), Italy. Manlio.Vinciguerra@embl.it
Musaro
Antonio
A
Rosenthal
Nadia
N
D000375:Aging / Q000502:physiology*; D000818:Animals; D006801:Humans; D009133:Muscular Atrophy / Q000378:metabolism*; D020966:Muscular Disorders, Atrophic / Q000503:physiopathology* / Q000628:therapy; D015398:Signal Transduction