American Diabetes Association
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AIFM2 is required for high-intensity aerobic exercise by promoting glucose utilization

posted on 2022-06-30, 18:55 authored by Hai P Nguyen, Sneha Damal Villivalam, Byung Chul Jung, Dongjoo You, Frances Lin, Danielle Yi, Anna Pi, Katherine Ma, Sunhee Jung, Sang-Hee Park, Cholsoon Jang, Hei Sook Sul, Sona Kang


Skeletal muscle is a major regulator of glycemic control at rest and glucose utilization increases drastically during exercise. Sustaining a high glucose utilization via glycolysis requires efficient replenishment of NAD+ in the cytosol. Apoptosis-inducing mitochondrion-associated factor 2 (AIFM2) has previously been shown to be a NADH oxidoreductase domain–containing flavoprotein to promote glycolysis for diet and cold-induced thermogenesis. Here, we find that AIFM2 is selectively and highly induced in glycolytic extensor digitorum longus (EDL) muscle during exercise. Overexpression of AIFM2 in myotubes is sufficient to elevate the NAD+/NADH ratio, increasing the glycolytic rate. Thus, overexpression of AIFM2 in skeletal muscle greatly increases exercise capacity, with increased glucose utilization. Conversely, muscle-specific Aifm2 depletion via in vivo transfection of hairpins against Aifm2 or tamoxifen-inducible haploinsufficiency of Aifm2 in muscles decreases exercise capacity and glucose utilization in mice. Moreover, muscle-specific introduction of NDE1, Saccharomyces cerevisiae external NADH dehydrogenase, NDE, ameliorates impairment in glucose utilization and exercise intolerance of the muscle-specific Aifm2 haploinsufficient mice. Together, we show a novel role for AIFM2 as a critical metabolic regulator for efficient utilization of glucose in glycolytic EDL muscles. 


Work was funded by R01 DK116008 (NIDDK) and P&F P30DK116074 (Stanford Diabetes Research Center) to SK and R01 DK123843 to HSS.