1722-P: Loss of Foxos in Muscle Maintains Strength and Mitochondrial Function during Aging, but Does Not Alter Glucose or Insulin Tolerance

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Muscle mitochondrial decline plays an important role in aging-related muscle weakness and is associated with insulin resistance. FoxO transcription factors are targets in insulin action and are determinants of longevity across species. However, the role of FoxOs in age-related strength and muscle mitochondrial decline is unknown. We measured strength, glucose/insulin tolerance, and muscle mitochondrial bioenergetics in 4.5- month (Young) and 24-month-old (Aged) muscle specific FoxO1/3/4 triple KO (TKO) and littermate control mice. Lean mass and muscle weights were increased 22-48% in young and aged TKO mice compared to age-matched controls. Ad libitum glucose levels were ∼12 mg/dL higher in aged groups compared to young, without differences between TKO and controls. Similarly, glucose and insulin tolerance were unchanged between TKO and control mice in both young and aged groups. While treadmill tests were not different between TKO and controls at either age, the aged control mice show a 20% decrease in max force of ankle dorsi-flexor muscles compared to young controls which was prevented in aged TKOs. Reductions in muscle mitochondrial respiration using glutamate/malate/succinate substrates were also prevented in aged TKO mice compared to aged controls. Mitochondrial Complex I activity was higher in both young and aged TKO compared to their respective controls. We did not see any differences in activity of citrate synthase, and protein expression of subunits from complex I and III, but not other complexes, showed an age-related decline in both TKO and control muscle. These data indicate that loss of FoxOs in muscle prevents age-related mitochondrial dysfunction and muscle weakness, without altering glucose or insulin tolerance, and may be a therapeutic target to prevent muscle atrophy. Disclosure C.M. Penniman: None. G. Bhardwaj: None. T. Junck: None. C. Boyer: None. J. Jena: None. J. Fuqua: None. V.A. Lira: None. B.T. ONeill: None.