Journal
EXPERIMENTAL GERONTOLOGY
Volume 155, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2021.111579
Keywords
Aging; mTOR; Metformin; Mitochondria; Healthspan
Categories
Funding
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine
- National Institutes of Health [R21AG067464]
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The study examined the effects of dietary rapamycin with or without metformin on skeletal muscle mitochondrial function in guinea pigs with age-related osteoarthritis. The results showed that both rapamycin and rapamycin with metformin decreased complex I-linked respiration and increased ADP sensitivity, suggesting potential implications for skeletal muscle function in osteoarthritis.
A decline in skeletal muscle mitochondrial function is associated with the loss of skeletal muscle size and function during knee osteoarthritis (OA). We have recently reported that 12-weeks of dietary rapamycin (Rap, 14 ppm), with or without metformin (Met, 1000 ppm), increased plasma glucose and OA severity in male Dunkin Hartley (DH) guinea pigs, a model of naturally occurring, age-related OA. The purpose of the current study was to determine if increased OA severity after dietary Rap and Rap+Met was accompanied by impaired skeletal muscle mitochondrial function. Mitochondrial respiration and hydrogen peroxide (H2O2) emissions were evaluated in permeabilized muscle fibers via high-resolution respirometry and fluorometry using either a saturating bolus or titration of ADP. Rap and Rap+Met decreased complex I (CI)-linked respiration and tended to increase ADP sensitivity, consistent with previous findings in patients with end-stage OA. The decrease in CI-linked respiration was accompanied with lower CI protein abundance. Rap and Rap+Met did not change mitochondrial H2O2 emissions. There were no differences between mitochondrial function in Rap versus Rap+Met suggesting that Rap was likely driving the change in mitochondrial function. This is the first inquiry into how lifespan extending treatments Rap and Rap+Met can influence skeletal muscle mitochondria in a model of age-related OA. Collectively, our data suggest that Rap with or without Met inhibits CI-linked capacity and increases ADP sensitivity in DH guinea pigs that have greater OA severity.
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