Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle

Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue, accompanied by a characteristic loss in the fastest, most powerful muscle fibers(1,2). The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia(3). We have generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mlgf-1), Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathological changes seen in other Igf-l transgenic models. Expression of CATA-2, a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic: of younger animals. The preservation of muscle architecture and age-independent regenerative capacity through localized mlgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.