Autophagy activation, not peroxisome proliferator‐activated receptor γ coactivator 1α, may mediate exercise‐induced improvements in glucose handling during diet‐induced obesity

Abstract

What is the central question of this study? What are the individual and combined effects of muscle-specific peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) overexpression and physical activity during high-fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle-specific PGC-1α overexpression provides no protection against lipid-overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC-1α content, protects against high-fat diet-induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise-induced protection from lipid overload. The prevalence of glucose intolerance is alarmingly high. Efforts to promote mitochondrial biogenesis through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) to mitigate glucose intolerance have been controversial. However, physical activity remains a primary means to alleviate the condition. The aim of this study was to determine the combined effects of muscle-specific overexpression of PGC-1α and physical activity on glucose handling during diet-induced obesity. Wild-type (WT, ∼20) and PGC-1α muscle transgenic (MCK-PGC-1α, ∼20) mice were given a Western diet (WD) at 8 weeks age and allowed to consume food ab libitum throughout the study. At 12 weeks of age, all animals were divided into sedentary (SED) or voluntary wheel running (VWR) interventions. At 7, 11 and 15 weeks of age, animals underwent glucose tolerance tests (GTT) and graded exercise tests (GXT). At 16 weeks of age, tissues were collected. At 11 weeks, the MCK-PGC-1α animals had 50% greater glucose tolerance integrated area under the curve compared with WT. However, at 15 weeks, SED animals also had greater GTT integrated area under the curve compared with VWR, regardless of genotype; furthermore, SED animals demonstrated reduced exercise capacity compared with earlier time points, which was not seen in VWR animals. Voluntary distance run per day was correlated with GTT in VWR-WT, but not VWR-MCK-PGC-1α mice. Voluntary wheel running and genotype independently resulted in a greater LC3II/LC3I ratio, suggesting enhanced autophagosome formation, which was correlated with exercise-induced improvements in GTT. In conclusion, artificially increasing mitochondrial content does not protect from lipid-induced pathologies nor does it augment exercise adaptations. Physical activity ameliorates the effects of lipid overload-induced glucose intolerance, an effect that appears to be related to enhanced activation of autophagy.

Exercise-Induced Benefits on Glucose Handling in a Model of Diet-Induced Obesity Are Reduced by Concurrent Nicotinamide Mononucleotide

“…Upregulation of Pgc1a expression may be attributed to regulation by both NAD + dependent SIRT1 deacetylation driven by NMN, and AMPK mediated phosphorylation driven by exercise [21,58]. In line with our results, a study examining muscle specific over-expression of Pgc1a did not find improvements in glucose handling in mice given a western diet, compared to physical exercise [59].…”

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

“…Exercise‐regulated autophagy also appears to involve mitochondrial autophagy receptors to target specific portions of the mitochondrial reticulum for degradation . Several studies have shown exercise increases the protein abundance of BNIP3, a mitochondrial autophagy receptor, in skeletal muscle . Additionally, the E3 ligase, Parkin localizes to the mitochondria after acute exercise to recruit autophagosomes .…”

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

“…Immunoblotting of proteins related to muscle protein synthesis and degradation were completed as previously described [ 45 , 46 , 47 ]. Protein concentrations were determined using an RC/DC commercial kit (Bio Rad, Hercules, CA, Cat# 5000121) and standard software (Gen5, BioTek, Winooski, VT).…”