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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.

Pubmed ID: 11175789

Authors

  • MusarĂ² A
  • McCullagh K
  • Paul A
  • Houghton L
  • Dobrowolny G
  • Molinaro M
  • Barton ER
  • Sweeney HL
  • Rosenthal N

Journal

Nature genetics

Publication Data

February 22, 2001

Associated Grants

None

Mesh Terms

  • Animals
  • Cachexia
  • Cell Aging
  • DNA-Binding Proteins
  • GATA2 Transcription Factor
  • Hypertrophy
  • Insulin-Like Growth Factor I
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal
  • Neurodegenerative Diseases
  • Organ Size
  • Protein Isoforms
  • Regeneration
  • Tissue Distribution
  • Transcription Factors