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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 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.

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Figure 1: Characterization of MLC/mIgf-1 transgenic mice.
Figure 2: MLC/mIgf-1 transgenic mice display pronounced muscle hypertrophy.
Figure 3: The hypertrophic action of mIgf-1 is preferentially restricted to the fastest muscles.
Figure 4: Intracellular signalling in MLC/mIgf-1 transgenic muscle.
Figure 5: MLC/mIgf-1 expression attenuates age-related genetic changes preserves skeletal muscle phenotype and regeneration in senescent mice.
Figure 6: Muscle regenerative capacity after injury is retained in senescent MLC/mIgf-1 transgenic mice.

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Acknowledgements

We thank J. Gonzales, E. Slonimsky and S. Zaltsman for generation and characterization of transgenic mouse lines and histological analysis; F. Depreux, C. Neville, L. Tsao and other members of the Rosenthal lab for advice and discussion; and G. Cossu for critical comments on this manuscript. A.M. was supported by a Research Development Award from the Muscular Dystrophy Association. This work was funded by grants to N.R. and L.S. from the National Institute on Aging and the Muscular Dystrophy Association, and by a grant to N.R. from NASA.

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Correspondence to Nadia Rosenthal.

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Musarò, A., McCullagh, K., Paul, A. et al. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27, 195–200 (2001). https://doi.org/10.1038/84839

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