Exercise leads to unfavourable cardiac remodelling and enhanced metabolic homeostasis in obese mice with cardiac and skeletal muscle autophagy deficiency

Abstract

Autophagy is stimulated by exercise in several tissues; yet the role of skeletal and cardiac muscle-specific autophagy on the benefits of exercise training remains incompletely understood. Here, we determined the metabolic impact of exercise training in obese mice with cardiac and skeletal muscle disruption of the Autophagy related 7 gene (Atg7h&mKO). Muscle autophagy deficiency did not affect glucose clearance and exercise capacity in lean adult mice. High-fat diet in sedentary mice led to endoplasmic reticulum stress and aberrant mitochondrial protein expression in autophagy-deficient skeletal and cardiac muscles. Endurance exercise training partially reversed these abnormalities in skeletal muscle, but aggravated those in the heart also causing cardiac fibrosis, foetal gene reprogramming, and impaired mitochondrial biogenesis. Interestingly, exercise-trained Atg7h&mKO mice were better protected against obesity and insulin resistance with increased circulating fibroblast growth factor 21 (FGF21), elevated Fgf21 mRNA and protein solely in the heart, and upregulation of FGF21-target genes involved in thermogenesis and fatty acid oxidation in brown fat. These results indicate that autophagy is essential for the protective effects of exercise in the heart. However, the atypical remodelling elicited by exercise in the autophagy deficient cardiac muscle enhances whole-body metabolism, at least partially, via a heart-brown fat cross-talk involving FGF21.

Downregulation of miR-26b-5p, miR-204-5p, and miR-497-3p Expression Facilitates Exercise-Induced Physiological Cardiac Hypertrophy by Augmenting Autophagy in Rats

“…Moreover, we found that the expression of other key autophagy-related genes such as ULK1, Atg12, and Atg4B, was significantly upregulated at the protein level in the left ventricle of rats with exercise-induced myocardial hypertrophy, whereas SQSTM1 (a marker of reduced autophagy) was downregulated. The findings are in concordance with previous results demonstrating that autophagy is enhanced by exercise training Yan et al, 2017;Li et al, 2019;Moradi et al, 2019), and endurance exercise provided cardioprotective effect by upregulating autophagy (Lee et al, 2017). Consistently, a highly activated autophagy was also observed in IGF-1 induced cardiomyocyte hypertrophy, which was agreed with that IGF-1 inhibition attenuated autophagosome formation (Renna et al, 2013).…”

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

“…High‐fat feeding results in an overload of lipids that drives lipid oxidation without high energy demands, putting stress on mitochondrial metabolism . High‐fat feeding in mice with a skeletal muscle knockout of Atg7, an autophagy machinery protein, impaired mitochondrial function, further supporting the role of autophagy in preserving mitochondrial function during metabolic stress. In our study, both WT and Bcl2 AAA mice had improved mitochondrial lipid oxidation capacity after high‐fat feeding, despite glucose intolerance.…”

Altered expression levels of autophagy-associated proteins during exercise preconditioning indicate the involvement of autophagy in cardioprotection against exercise-induced myocardial injury

“…Autophagic proteins may fail to be properly translocated during excessive exercise, e.g., damaged mitochondria and misfolded proteins, which leads to the reduction of autophagic efficiency [6,12]. Yan, et al [35] have reported that maintaining a normal level of autophagy during exercise is essential to cardiac metabolism and cardioprotection. Our results show that the EEP group has high-intensity exerciselike autophagic induction, despite the decreased expression of p62 and the increased ratio of LC3II/ LC3I.…”