Mitochondrial adaptations to exercise do not require Bcl2‐mediated autophagy but occur with BNIP3/Parkin activation

Abstract

Understanding the mechanisms regulating mitochondrial respiratory function and adaptations to metabolic challenges, such as exercise and high dietary fat, is necessary to promote skeletal muscle health and attenuate metabolic disease. Autophagy is a constitutively active degradation pathway that promotes mitochondrial turnover and transiently increases postexercise. Recent evidence indicates Bcl2 mediates exercise‐induced autophagy and skeletal muscle adaptions to training during high‐fat diet. We determined if improvements in mitochondrial respiration due to exercise training required Bcl2‐mediated autophagy using a transgenic mouse model of impaired inducible autophagy (Bcl2AAA). Mitochondrial adaptations to a treadmill exercise training protocol, in either low‐fat or high‐fat diet fed mice, did not require Bcl2‐mediated autophagy activation. Instead, training increased protein synthesis rates and basal autophagy in the Bcl2AAA mice, while acute exercise activated BNIP3 and Parkin autophagy. High‐fat diet stimulated lipid‐specific mitochondrial adaptations. These data demonstrate increases in basal mitochondrial turnover, not transient activation with exercise, mediate adaptations to exercise and high‐fat diet.

Short-Term High-Fat Feeding Does Not Alter Mitochondrial Lipid Respiratory Capacity but Triggers Mitophagy Response in Skeletal Muscle of Mice

“…These data suggest that several days of lipid overload activates upstream mitophagy signals, which may be mediated through ROS production, as an initial signal for skeletal muscle mitochondria to adapt to dietary lipid. Our previous study demonstrated that compared with low-fat diet, mice consuming high-fat diet for 12 weeks had greater oxidative phosphorylation capacity specific for lipid substrates (6). In the current study, we demonstrated dynamic changes, specific to lipid respiration, within shorter time periods of 3 to 7 days.…”

“…Mice consumed either a low-fat diet (LFD; D12450J; Research Diets) or high-fat diet (HFD; D12492; Research Diets) ad libitum for 3 days and 7 days to measure acute effects on mitochondrial respiration. A third group consumed diets for 12 weeks to investigate long-term changes in protein abundance and signaling, but not respiration because long-term changes in respiration have been well-documented by our group ( 6 , 22 ). The percent kilocalories from total fat (from lard)/carbohydrate/protein was 10/70/20 for the LFD and 60/20/20 for the HFD.…”

“…Based on our previous report of HFD and LFD feeding in the same strain of mice, lipid respiration normalized for mitochondrial protein abundance for LFD mice was Mean (SD) of 1.3 (0.38) and HFD was 1.8 (0.76) ( 6 ). Using n=5 per group, SD of 0.4, α at 0.05 and 1-β of either 0.8 or 0.5, an un-paired t-test could detect differences of 0.81 and 0.56.…”

“…Previous work, focused on heart tissue, demonstrated that high-fat diet induces mitophagy in a Parkin-dependent manner, as a protective mechanism against diabetic cardiomyopathy ( 21 ). Our previous work in mice demonstrated Bnip3, but not Parkin-mediated mitophagy, was upregulated in skeletal muscle after long-term high-fat feeding ( 6 ), suggesting mitophagy is a contributing mechanism to mitochondrial adaptations to lipid overload. Lipid-induced mitochondrial ROS production may be a contributing stimulus of mitophagy mechanisms during initial mitochondrial adaptations to high-fat feeding.…”

“…High-fat over-feeding in mice induces whole-body glucose intolerance within 3 days and skeletal muscle insulin resistance by 3 weeks ( 5 ), demonstrating a rapid response in skeletal muscle to high-fat feeding. Long-term (3-4 months) diet studies with increased dietary lipid availability increases mitochondrial fatty acid oxidation capacity ( 6 ) due to increases in mitochondrial protein abundance ( 7 , 8 ) and enzyme activity ( 9 ). However, alterations in the mitochondrial regulatory pathways within a shorter time frame (< 1 week) are not as well characterized.…”