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bioRxiv · 10.1101/2021.09.16.460597

Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice

Balasubramanian, P.·Schaar, A. E.·Gustafson, G. E.·Smith, A. B.·Howell, P. R.·Greenman, A.·Baum, S.·Colman, R. J.·Lamming, D. W.·Diffee, G. M.·Anderson, R.
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Abstract

The loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently there are no pharmacological therapeutic interventions for sarcopenia. Here we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator activated receptor gamma coactivator 1 alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.

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Balasubramanian, P., Schaar, A. E., Gustafson, G. E., Smith, A. B., Howell, P. R., Greenman, A., Baum, S., Colman, R. J., Lamming, D. W., Diffee, G. M., Anderson, R.. 2021-09-17. Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice. https://doi.org/10.1101/2021.09.16.460597

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