Effects of MTOR Signaling in Muscle-Specific Irs1/2 Knockout Mice

Disruption of Irs1 and Irs2 expression in skeletal and cardiac muscle (MDKO mice) caused death from dilated cardiomyopathy within the first 30 days of life. MDKO showed muscle atrophy but were not glucose intolerant, despite impaired muscle glucose uptake. Beiging of white adipose fat increased glucose uptake into white adipose tissue of MDKO mice, and glucose uptake into brown adipose was also increased. Knockout of atrophy-driving genes FoxO1 and FoxO3a in MDKO mice (MQKO mice) extended life span to 70 days, when MQKO mice died with cardiomyopathy. High fat diet feeding increased life span in both MDKO and MQKO mice; however, genetic activation of the MTOR pathway in muscle of MDKO mice by Tsc1 knockout (MTKO mice) increased life span to 220 days. Regardless, MTKO mice developed cardiac hypertrophy with reduced ejection fraction by 24 weeks. Cardiac glucose uptake in MTKO mice was impaired during non-insulin as well as during insulin-stimulated conditions. Moreover, fat mass of MTKO mice decreased over time, implying a shift in consumption by MTKO hearts from glucose to fatty acids as source for cardiac energy. Tracing of radiolabeled palmitic acid did not support increased cardiac fatty acid uptake in MTKO mice; however, expression of lactate transporters was significantly elevated in MTKO hearts and circulating lactate generated by skeletal muscle was significantly reduced, indicating a potential use of lactate in MTKO hearts. These results show more robust effects of activating the MTOR pathway in insulin resistant hearts of MDKO mice rather than manipulating atrophy-related genes FoxO1/3a to counter early death from cardiomyopathy. Furthermore, activated MTOR signaling potentiated a metabolic switch in MDKO hearts. Disclosure O.Stoehr: None. K.D.Copps: None. R.Tao: None. M.F.White: Board Member; Housey Pharma.