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. 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.
Musarò
A
A
Cardiovascular Research Center, Massachusetts General Hospital-East, Charlestown, Massachusetts, USA.
McCullagh
K
K
Paul
A
A
Houghton
L
L
Dobrowolny
G
G
Molinaro
M
M
Barton
E R
ER
Sweeney
H L
HL
Rosenthal
N
N
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
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D020033:Protein Isoforms; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I