Mitochondrial regulation in skeletal muscle: A role for non‐coding RNAs?

Abstract

Skeletal muscle is a highly metabolic tissue characterized by high mitochondrial abundance. As such, skeletal muscle homeostasis relies on the tight control of mitochondrial gene expression to ensure efficient mitochondrial function. Mitochondria retain a conserved genome from prokaryotic ancestors, and mitochondrial gene regulation relies on communication between mitochondrial- and nuclear-encoded transcripts. Small and long non-coding RNAs (ncRNAs) have regulatory roles in the modulation of gene expression. Emerging evidence demonstrates that regulatory ncRNAs, particularly microRNAs (miRNAs) and long ncRNAs (lncRNAs), localize within the mitochondria in diverse physiological and pathological states. These molecules present intriguing possibilities for the regulation of mitochondrial gene expression. Current research suggests that all known miRNAs are encoded by the nuclear genome but can target mitochondrial genes. Initial investigations demonstrate direct interactions between the muscle-enriched miR-1 and miR-181c and mitochondrial transcripts, suggesting advanced roles of miRNAs in mitochondrial gene regulation. This review draws evidence from the current literature to discuss the hypothesis that a level of ncRNA-mediated gene regulation, in particular miRNA-mediated gene regulation, takes place in the mitochondria. Although ncRNA-mediated regulation of the mitochondrial genome is a relatively unexplored field, it presents exciting possibilities to further our understanding of mitochondrial metabolism and human muscle physiology.

Extracellular vesicular miRNA expression is not a proxy for skeletal muscle miRNA expression in males and females following acute, moderate intensity exercise

“…Although the blood sampling method used in this study is replicated throughout the literature (D'Souza et al, 2018;Frühbeis et al, 2015;Lovett et al, 2018), the limitation of this study, and ultimately many in this field, is that blood samples and muscle biopsies were taken from different parts of the body. By examining muscle-enriched miRNA species (Silver, Wadley, & Lamon, 2018), the likelihood that the miRNAs examined were released by skeletal muscle is increased; however, these species are also enriched in cardiac muscle. It must be recognized that this is a limitation of this study and we cannot conclusively determine the origin of the isolated EVs.…”

PGC-1α Methylation, miR-23a, and miR-30e Expression as Biomarkers for Exercise- and Diet-Induced Mitochondrial Biogenesis in Capillary Blood from Healthy Individuals: A Single-Arm Intervention

“…Furthermore, it has been shown that the expression of some miRNAs differs after exercise, which could affect skeletal muscle regeneration, gene transcription, and mitochondrial biogenesis [ 13 , 15 ]. Often-discussed examples are miR-23, miR-696, and miR-30e, which have PGC-1α as a predicted target [ 16 , 17 , 18 ]. Endurance training seems to downregulate miR-23a expression, which promotes mitochondrial biogenesis by the upregulation of PGC-1α .…”

Purification of mitochondria from skeletal muscle tissue for transcriptomic analyses reveals localisation of nuclear-encoded non-coding RNAs

“…To meet these dynamic bioenergetic demands, skeletal muscle is densely populated with mitochondria (Russell et al, 2014). Thus, gaining a greater understanding of the RNA profile within muscle mitochondria may yield important insights into the cellular biology and aetiology of diverse metabolic diseases characterised by mitochondrial dysfunction, such as diabetes mellitus and chronic myopathies (Silver et al, 2018). Here, we report a method for isolating and optimising the enzymatic purification of mitochondria from rodent muscle cells or tissues.…”

“…Mitochondria are comprised of proteins encoded by both the nuclear and mitochondrial genomes, but nuclear-encoded RNAs are not usually localised within mitochondria. A small number of specific RNAs, such as microRNAs (miRNAs) (Barrey et al, 2011, Sripada et al, 2012, Das et al, 2012) and long non-coding RNAs (lncRNAs) (Noh et al, 2016) can however be imported into mitochondria (Silver et al, 2018) via the polynucleotide phosphorylase (Wang et al, 2010) and other putative transport mechanisms (reviewed in Silver et al, 2018). Because ncRNAs have the ability to regulate various transcriptional and translational processes relating to mitochondrial function, it is of interest to determine which of these may localise within mitochondria in order to understand the nature of their potential regulatory actions.…”