Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle
Antonio Musarò1, 2, Karl McCullagh1, Angelika Paul1, Leslie Houghton1, Gabriella Dobrowolny2, Mario Molinaro2, Elisabeth R. Barton3, H. L Sweeney3
& Nadia Rosenthal1
1
Cardiovascular Research Center, Massachusetts General Hospital-East, Charlestown, Massachusetts, USA.
2
Department of Histology and Medical Embryology, University of Rome "La Sapienza", Rome, Italy.
3
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
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 fibers1,
2. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia3. 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 (mIgf-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-1 transgenic models. Expression of GATA-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 mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.
