Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities

• Published in: Aging cell 2024-09, Vol.23 (9), p.e14235-n/a
• Main Authors: Bubak, Matthew P., Davidyan, Arik, O'Reilly, Colleen L., Mondal, Samim A., Keast, Jordan, Doidge, Stephen M., Borowik, Agnieszka K., Taylor, Michael E., Volovičeva, Evelina, Kinter, Michael T., Britton, Steven L., Koch, Lauren G., Stout, Michael B., Lewis, Tommy L., Miller, Benjamin F.
• Format: Article
• Language: English
• Subjects: Aerobic capacity; Age; Aging; Animals; Body composition; Body mass index; Cancer; Chronic illnesses; Clinical outcomes; deuterium oxide; Diabetes; Disease; Exercise; geroscience; healthspan; Hypoglycemic Agents - pharmacology; Kinases; Male; Metabolism; Metformin; Metformin - pharmacology; Mitochondria; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Mortality; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Musculoskeletal system; Physical Conditioning, Animal; Physical fitness; Protein biosynthesis; protein synthesis; Proteins; proteomics; Rats; Respiration; Running; Skeletal muscle
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.14235

The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan extension metformin will also be used in periods of good health. To understand the potential context specificity of metformin treatment on skeletal muscle, we used a rat model (high‐capacity runner/low‐capacity runner [HCR/LCR]) with a divide in intrinsic aerobic capacity. Outcomes of metformin treatment differed based on baseline intrinsic mitochondrial function, oxidative capacity of the muscle (gastroc vs soleus), and the mitochondrial population (intermyofibrillar vs. subsarcolemmal). Metformin caused lower ADP‐stimulated respiration in LCRs, with less of a change in HCRs. However, a washout of metformin resulted in an unexpected doubling of respiratory capacity in HCRs. These improvements in respiratory capacity were accompanied by mitochondrial remodeling that included increases in protein synthesis and changes in morphology. Our findings raise questions about whether the positive findings of metformin treatment are broadly applicable. We tested if the effects of metformin were context specific in skeletal muscle using a rat model (high‐capacity and low‐capacity runners: HCRs/LCRs) with a divide in intrinsic aerobic capacity. Metformin lowered mitochondrial respiration, but a washout of metformin resulted in a doubling of respiratory capacity in HCRs, with no effect in LCRs. These changes in respiratory capacity were accompanied by strain‐specific mitochondrial remodeling, which draws into question whether the positive findings of metformin can be applied to all metabolic conditions.