2515-P: FoxOs Mediate Mitochondrial Decline, ANT1 Suppression, and Weakness in Response to Insulin and IGF-1 Receptor Deletion in Adult Skeletal Muscle

Introduction and Objective: Skeletal muscle weakness and mitochondrial dysfunction are hallmarks of uncontrolled diabetes. Our prior work showed muscle specific deletion of Insulin receptor (IR) and IGF-1 (IGFR) impairs respiration and ATP production. FoxO transcription factors are activated in response to loss of insulin action and contribute to mitochondrial decline in skeletal muscle. Methods: To define the time dependent effects of IR/IGFR loss and requirement of FoxOs, we tested mitochondrial function in tamoxifen-inducible, muscle-specific IR (Ind-MIRKO) or IR/IGF1R knockout (Ind-MIGIRKO) and performed rescue by combined IR/IGF1R with FoxO1/3/4 quintuple knockout (Ind-QKO) mice. Results: 90 days after tamoxifen KO, Ind-MIRKO mice showed decreased treadmill running and grip strength, but not at Day 21. Permeabilized soleus fiber respiration and ATP production were decreased 33% and 14%, respectively, at Day 90. Ind-MIGIRKO showed decreased grip strength, treadmill, maximal tibialis anterior torque, mitochondrial respiration and ATP production at both Day 21 and 90, all of which was rescued in Ind-QKO. At day 21, Ind-MIGIRKO showed decreased SLC25A4 (aka ANT1) expression by 56%. By day 90, Km of ADP increased by 36% in Ind-MIGIRKO compared to controls indicating decreased ADP sensitivity. However, IC50 using an ANT1 inhibitor was not changed in Ind-MIGIRIKO soleus and re-expression of ANT1 by plasmid electroporation in gastrocnemius did not rescue ATP production in Ind-MIGIRKO mitochondria. Conclusion: Thus, inducible deletion of IR or IR/IGFR in adult muscle causes muscle weakness and mitochondrial dysfunction that is FoxO-dependent. While ANT1 is decreased with IR/IGF1R deletion, restoring ANT1 alone is not sufficient to rescue ATP production. Disclosure E. Stammler: None. C. Penniman: None. J. Jena: None. G. Bhardwaj: None. B.T. O'Neill: Stock/Shareholder; Current; Johnson & Johnson, Bristol-Myers Squibb Company, Pfizer Inc.