title: Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle.
abstract: 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. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia. 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.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital-East, Charlestown, Massachusetts, USA.
authors.forename: A
authors.initials: A
authors.lastname: Musarò
authors.forename: K
authors.initials: K
authors.lastname: McCullagh
authors.forename: A
authors.initials: A
authors.lastname: Paul
authors.forename: L
authors.initials: L
authors.lastname: Houghton
authors.forename: G
authors.initials: G
authors.lastname: Dobrowolny
authors.forename: M
authors.initials: M
authors.lastname: Molinaro
authors.forename: E R
authors.initials: ER
authors.lastname: Barton
authors.forename: H L
authors.initials: HL
authors.lastname: Sweeney
authors.forename: N
authors.initials: N
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D002100:Cachexia; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics; D050989:GATA2 Transcription Factor; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000502:physiology*; D019636:Neurodegenerative Diseases; D009929:Organ Size; D020033:Protein Isoforms; D012038:Regeneration; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D020033:Protein Isoforms; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I