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Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice

View ORCID ProfilePriya Balasubramanian, Anne E. Schaar, View ORCID ProfileGrace E. Gustafson, Alex B. Smith, Porsha R. Howell, Angela Greenman, Scott Baum, Ricki J. Colman, View ORCID ProfileDudley W. Lamming, Gary Diffee, View ORCID ProfileRozalyn M. Anderson
doi: https://doi.org/10.1101/2021.09.16.460597
Priya Balasubramanian
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin Madison, WI, United States
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Anne E. Schaar
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin Madison, WI, United States
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Grace E. Gustafson
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin Madison, WI, United States
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Alex B. Smith
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin Madison, WI, United States
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Porsha R. Howell
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin Madison, WI, United States
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Angela Greenman
2Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States
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Scott Baum
3Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States
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Ricki J. Colman
3Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States
4Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, United States
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Dudley W. Lamming
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin Madison, WI, United States
5Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, United States
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Gary Diffee
2Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States
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Rozalyn M. Anderson
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin Madison, WI, United States
5Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, United States
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  • For correspondence: rozalyn.anderson@wisc.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 17, 2021.
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Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice
Priya Balasubramanian, Anne E. Schaar, Grace E. Gustafson, Alex B. Smith, Porsha R. Howell, Angela Greenman, Scott Baum, Ricki J. Colman, Dudley W. Lamming, Gary Diffee, Rozalyn M. Anderson
bioRxiv 2021.09.16.460597; doi: https://doi.org/10.1101/2021.09.16.460597
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Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice
Priya Balasubramanian, Anne E. Schaar, Grace E. Gustafson, Alex B. Smith, Porsha R. Howell, Angela Greenman, Scott Baum, Ricki J. Colman, Dudley W. Lamming, Gary Diffee, Rozalyn M. Anderson
bioRxiv 2021.09.16.460597; doi: https://doi.org/10.1101/2021.09.16.460597

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