Increased IGF-1 in muscle modulates the phenotype of severe SMA mice

Marta Bosch-Marcé, Claribel D. Wee, Tara L. Martinez, Celeste E. Lipkes, Dong W. Choe, Lingling Kong, James P. Van Meerbeke, Antonio Musarò, Charlotte J. Sumner

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor func- tion and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myo- genic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival 5 14 versus 10 days, respectively, log-rank P 5 0.025). Surprisingly, this was not associated with a significant improve- ment in motor behavior. Treatment of both mIGF-1NEG and mIGF-1POS SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that thera- peutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients.

Original languageEnglish (US)
Article numberddr067
Pages (from-to)1844-1853
Number of pages10
JournalHuman molecular genetics
Issue number9
StatePublished - May 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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