Regulatory networks coordinating mitochondrial quality control in skeletal muscle

Abstract

The adaptive plasticity of mitochondria within skeletal muscle is regulated by signals converging on a myriad of regulatory networks that operate during conditions of increased (i.e. exercise) and decreased (inactivity, disuse) energy requirements. Notably, some of the initial signals that induce adaptive responses are common to both conditions, differing in their magnitude and temporal pattern, to produce vastly opposing mitochondrial phenotypes. In response to exercise, signaling to PGC-1α and other regulators ultimately produces an abundance of high quality mitochondria, leading to reduced mitophagy and a higher mitochondrial content. This is accompanied by the presence of an enhanced protein quality control system that consists of the protein import machinery as well chaperones and proteases termed the UPRmt. The UPRmt monitors intra-organelle proteostasis, and strives to maintain a mito-nuclear balance between nuclear- and mtDNA-derived gene products via retrograde signaling from the organelle to the nucleus. In addition, antioxidant capacity is improved, affording greater protection against oxidative stress. In contrast, chronic disuse conditions produce similar signaling but result in decrements in mitochondrial quality and content. Thus, the interactive cross-talk of the regulatory networks that control organelle turnover during wide variations in muscle use and disuse remain incompletely understood, despite our improving knowledge of the traditional regulators of organelle content and function. This brief review acknowledges existing regulatory networks and summarizes recent discoveries of novel biological pathways involved in determining organelle biogenesis, dynamics, mitophagy, protein quality control and antioxidant capacity, identifying ample protein targets for therapeutic intervention that determine muscle and mitochondrial health.

Insight into the Molecular Signature of Skeletal Muscle Characterizing Lifelong Football Players

“…These proteins covered a variety of mitochondrial functions, as already described for high-functioning octogenarian master athletes [ 35 ], and supported the established knowledge that regular PA improves mitochondrial function [ 37 , 38 , 39 , 40 , 41 ], counteracting the decline in muscle strength and mass and in neuromuscular control [ 42 , 43 ]. In fact, the exercise-mediated coordinated expression of mitochondrial species activates mitochondrial biogenesis, which affects several functions within the organelle and triggers several signaling pathways [ 44 , 45 ] that are able to induce specific adaptations to the mechanical stimuli; among these, the increased oxidative capacity is a well-recognized hallmark of PA-mediated adaptation in the mitochondria [ 41 , 46 , 47 ]. Accordingly, by using different bioinformatic tools, in the overexpressed subset of this study, mitochondrial proteins involved in the oxidative metabolism were found, such as NDUFA7, NDUFA9, SUCLG1, UQCRH, ACAA2, ACADSB and ATP5J, confirming the previous findings.…”

Flavanol-Rich Cocoa Supplementation Inhibits Mitochondrial Biogenesis Triggered by Exercise

“…We observed a trend for a decrease in the expression levels of Nrf2 in the cocoa-supplemented animal model, which were significantly increased by exercise. Nrf2 is key in the coordination of redox mechanisms triggered by exercise [ 61 ], and is involved in the expression of antioxidant enzymes such as SOD [ 62 ]. Although it was not possible to measure the expression of Nrf2 in our athlete study, we did observe a decrease in systemic SOD activity, which supports the idea that cocoa intake modifies the expression of Nrf2 .…”

Aerobic Exercise Training Rejuvenates the Human Skeletal Muscle Methylome Ten Years after Breast Cancer Treatment and Survival

“…Indeed, a reduction in gene expression associated with cell cycle could impair growth and normal muscle maintenance (reviewed in [50]). Therefore, hypermethylation and suppression of gene expression within proteolysis, mitophagy and autophagy pathways, while perhaps counterintuitive as increases in these processes are observed in muscle wasting conditions such as cancer cachexia [51-53], this data is perhaps suggestive of a dysregulation in the genes involved in protein quality control processes in the SkM of cancer survivors. Where an inability to properly remove damaged cellular and mitochondrial proteins could contribute to impaired muscle function and quality [53, 54].…”

“…Therefore, hypermethylation and suppression of gene expression within proteolysis, mitophagy and autophagy pathways, while perhaps counterintuitive as increases in these processes are observed in muscle wasting conditions such as cancer cachexia [51-53], this data is perhaps suggestive of a dysregulation in the genes involved in protein quality control processes in the SkM of cancer survivors. Where an inability to properly remove damaged cellular and mitochondrial proteins could contribute to impaired muscle function and quality [53, 54]. For example, blocking autophagy is unable to spare muscle mass in mice with cancer cachexia, due to its role in protein quality control [55].…”