Regulation of Exercise-Induced Autophagy in Skeletal Muscle

Abstract

Purpose of review: Physical exercise is a highly effective method to prevent several pathogenic conditions, such as obesity, type 2 diabetes and cardiovascular diseases, largely due to metabolic adaptations induced by exercise in skeletal muscle. Yet how exercise induces the beneficial effects in muscle remains to be fully elucidated. Autophagy is a lysosomal degradation pathway that regulates nutrient recycling, energy production and organelle quality control. The autophagy pathway is upregulated in response to stress during exercise and muscle contraction, and may be an important mechanism mediating exercise-induced health benefits.

Recent findings: A number of studies have indicated that physical exercise induces non-selective autophagy and selective mitophagy in skeletal muscle in animal models and humans. The AMPK-ULK1 and the FoxO3 signaling pathways play an essential role in the activation of the upstream autophagy machinery in skeletal muscle during exercise. The autophagy activity is required for health benefits of exercise, as in different autophagy-deficient mouse lines exercise-induced effects are abolished.

Summary: This review aims to summarize and highlight the most recent findings on the role of autophagy in muscle maintenance, the molecular pathways that upregulate autophagy during exercise, and the potential functions of exercise-induced autophagy and mitophagy in skeletal muscle.

Keywords: AMP-activated protein kinase; Autophagy; Forkhead box protein transcription factor 3; Mitophagy; Physical exercise; Skeletal muscle.

Figure 1

A. Schematic representation of the non-selective autophagy pathway. After the nucleation and elongation step, the mature autophagosome containing a portion of cytoplasm fuses with the lysosome, in which cellular contents are degraded. B. Schematic representation of mitophagy, in which the autophagy machinery selectively recognizes either cytosolic receptors (such as p62 recruited by the PINK1\Parkin pathway) that bind to ubiquitinated mitochondria, or mitochondrial outer-membrane receptor proteins, such as BNIP3 and FUNC1. Mitochondria are then degraded in the autolysosome. C. Major upstream signaling pathways that induce autophagy and mitophagy during exercise. Activation of AMPK stimulates autophagy by inhibiting mTOR and inducing the ULK1/2 kinase. AMPK also promotes the expression of the FoxO3 transcription factor, which upregulates multiple autophagy genes at the transcriptional level. Unknown circulating factors may as well contribute to autophagy induction after exercise.