High-fat Diet Increases ETF Synthesis And Lipid Respiration In Muscle During Training In Female Mice

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Aerobic training reverses the detrimental accumulation of muscle lipids during high-fat diet (HFD)-induced obesity through unclear mechanisms. The electron-transferring flavoproteins (ETF) transfer reducing equivalents from beta-oxidation into the electron transfer system. A potential mechanism for benefits on lipid metabolism is that exercise may stimulate the synthesis of ETF proteins to increase lipid respiration. Female mice have a tendency for greater mitochondrial abundance and lipid respiration that may underlie resilience to HFD versus males. PURPOSE: Our purpose was to determine ETF synthesis and respiratory function to exercise and HFD in females. We hypothesized that exercise during HFD would increase ETF synthesis and abundance versus HFD or exercise alone. METHODS: Female C57BL/6 J mice (n = 15 per group) consumed HFD or low-fat diet (LFD) for 4 weeks then remained sedentary (SED) or completed 8 weeks of treadmill training (EX). Mice consumed D2O in drinking water during the final 14 days then we measured deuterium enrichment in targeted peptides to calculate the synthesis rates of ETF subunits. We determined lipid-supported respiration in isolated mitochondria and measured RNA and protein abundance for ETFA, ETFB and ETF dehydrogenase (ETFDH). RESULTS: HFD had a main effect for greater synthesis rates for ETFA and ETFDH (+71% and + 75%, P < 0.01 versus LFD) while EX had a main effect for greater synthesis of ETFB and ETFDH (+56 and + 55%, P < 0.01 vs SED). HFD had a main effect, without modification by exercise, for higher lipid respiration (+39%, P = 0.018 vs LFD) when expressed in absolute units, but not after normalizing to mitochondrial protein abundance. There were no detectable changes to ETF protein abundance via targeted proteomics. There were small main effects of HFD for higher RNA abundance for ETFA (+5%, P = 0.026), ETFB (+6%, P < 0.01), and ETFDH (5%, P < 0.01). CONCLUSIONS: Exercise did not modify the effect of HFD to increase lipid respiration in female mice. The greater synthesis of ETF during HFD indicates intrinsic remodeling of mitochondria to high-dietary fat availability. The exercise-induced benefits on lipid metabolism appears to be a net result of several oxidation proteins in addition to ETF. Funding by OHSU Medical Research Foundation and Nathan Shock Pilot Grant (NIH P30 AG050911).

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