43-OR: Muscle mTOR Activation Attenuates Cardiomyopathy and Extends Lifespan in Muscle-Specific IRS1/IRS2 Knockout Mice

Introduction and Objective: We investigated the role of insulin/IGF1 signaling in cardiac function and lifespan of MDKO mice (Irs1^L/L•Irs2^L/L•Cre^Mck) generated by MCK (muscle creatine kinase) driven Cre expression in striated and cardiac muscle.Methods: MDKO mice died by 30 days of age with severe cardiomyopathy. Deletion of FoxO1 and FoxO3a in MDKO mice (MQKO mice) slowed progression of cardiomyopathy, extending lifespan to 80 days. MDKO mice showed severely reduced Akt→mTOR signaling so we investigated whether genetic activation of mTorc1 in MTKO mice (Irs1^L/L•Irs2^L/L•Tsc1^L/L•Cre^Mck) could attenuate cardiomyopathy and extend lifespan.Results: Lifespan increased to 220 days, but MTKO mice showed cardiac dysfunction (reduced ejection fraction) at 112 days of age. Full activation of mTorc1 appeared to be essential to compensate for insulin/IGF resistance because partial activation of mTorc1 caused severe cardiomyopathy and death of MDKO•Tsc1^L/+ mice by 40 days of age. Unexpectedly, HFD (high fat diet) feeding of MDKO•Tsc1^+/- mice restored the lifespan from 40 to 220 days. HFD also significantly increased lifespan of MQKO mice from 80 to 178 days; however, HFD did not increase the lifespan of MTKO mice beyond 220 days. Thus, HFD or muscle Tsc1 deletion appears to extend lifespan during chronic insulin/IGF1 resistance. Cardiac glucose uptake was significantly reduced in MTKO mice; however, cardiac fatty acid uptake did not increase. Lactate might nourish the cardiac muscle of MTKO mice as cardiac lactate transporters increased significantly while circulating lactate decreased. Consistently, lactate treatment of MTKO mice corrected cardiac function, including ejection fraction and structural cardiac parameters (left ventricle internal diameter). MTKO mice fed lactate survived until the experiment was terminated at 280 days.Conclusion: Overall, these results suggest that the progression of fatal cardiomyopathy in MDKO mice was rescued by mTorc1 activity through genetic and/or nutritional manipulation.

O. Stoehr: None. R. Tao: None. K.D. Copps: None. M.F. White: Board Member; HPRL (Housey Pharmaceutical Research Laboratory).



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