microRNAs: Modulators of the underlying pathophysiology of sarcopenia?

Skeletal muscle homeostasis depends on an intricate balance between muscle hypertrophy, atrophy and regeneration. As we age, maintenance of muscle homeostasis is perturbed, resulting in a loss of muscle mass and function, termed sarcopenia. Individuals with sarcopenia exhibit impaired balance, increased falls (leading to subsequent injury) and an overall decline in quality of life. The mechanisms mediating sarcopenia are still not fully understood but clarity in our understanding of the precise pathophysiological changes occurring during skeletal muscle ageing has improved dramatically. Advances in transcriptomics has highlighted significant deregulation in skeletal muscle gene expression with ageing, suggesting epigenetic alterations may play a crucial and potentially causative role in the skeletal muscle ageing process. microRNAs (miRNAs, miRs), novel regulators of gene expression, can modulate many processes in skeletal muscle, including myogenesis, tissue regeneration and cellular programming. Expression of numerous evolutionary conserved miRNAs is disrupted in skeletal muscle with age. Given that a single miRNA can simultaneously affect the functionality of multiple signaling pathways, miRNAs are potent modulators of pathophysiological changes. miRNA-based interventions provide a promising new therapeutic strategy against alterations in muscle homeostasis. The aim of this review is two-fold; firstly to outline the latest understanding of the pathophysiological alterations impacting the deregulation of skeletal muscle mass and function with ageing, and secondly, to highlight the mounting evidence for a role of miRNAs in modulating muscle mass, and the need to explore their specific role in sarcopenia

Major histocompatibility complex I‐induced endoplasmic reticulum stress mediates the secretion of pro‐inflammatory muscle‐derived cytokines

© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: This is an open access article under the terms of the Creative Commons Attribution License,https://creativecommons.org/licenses/by/4.0/Major histocompatibility complex (MHC) I is an important component of intracellular antigen presentation. However, improper expression of MHC I upon the cell surface has been associated with several autoimmune diseases. Myositis is a rare acquired autoimmune disease which targets skeletal muscle, and MHC I overexpression on the surface of muscle fibres and immune cell infiltration are clinical hallmarks. MHC I overexpression may have an important pathogenic role, mediated by the activation of the endoplasmic reticulum (ER) stress response. Given the evidence that muscle is a diverse source of cytokines, we aimed to investigate whether MHC I overexpression can modify the profile of muscle‐derived cytokines and what role the ER stress pathway may play. Using C2C12 myoblasts we overexpressed MHC I with a H‐2kb vector in the presence or absence of salubrinal an ER stress pathway modifying compound. MHC I overexpression induced ER stress pathway activation and elevated cytokine gene expression. MHC I overexpression caused significant release of cytokines and chemokines, which was attenuated in the presence of salubrinal. Conditioned media from MHC I overexpressing cells induced in vitro T‐cell chemotaxis, atrophy of healthy myotubes and modified mitochondrial function, features which were attenuated in the presence of salubrinal. Collectively, these data suggest that MHC I overexpression can induce pro‐inflammatory cytokine/chemokine release from C2C12 myoblasts, a process which appears to be mediated in‐part by the ER stress pathway.Peer reviewe

Age-related Changes in miR-143-3p:Igfbp5 Interactions Affect Muscle Regeneration

A common characteristic of aging is defective regeneration of skeletal muscle. The molecular pathways underlying age-related decline in muscle regenerative potential remain elusive. microRNAs are novel gene regulators controlling development and homeostasis and the regeneration of most tissues, including skeletal muscle. Here, we use satellite cells and primary myoblasts from mice and humans and an in vitro regeneration model, to show that disrupted expression of microRNA-143-3p and its target gene, Igfbp5, plays an important role in muscle regeneration in vitro. We identified miR-143 as a regulator of the insulin growth factor-binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR-143 and its target gene is disrupted in satellite cells from old mice. Moreover, we show that downregulation of miR-143 during aging may act as a compensatory mechanism aiming at improving myogenesis efficiency; however, concomitant upregulation of miR-143 target gene, Igfbp5, is associated with increased cell senescence, thus affecting myogenesis. Our data demonstrate that dysregulation of miR-143-3p:Igfbp5 interactions in satellite cells with age may be responsible for age-related changes in satellite cell function

MicroRNAs as potential therapeutic targets for muscle wasting during cancer cachexia

Purpose of reviewMuscle wasting in cancer cachexia remains an unmet clinical need due to lack of effective therapies associated with the complexity of the disease. Here, we discuss microRNAs, robust regulators of the expression of multiple genes, only recently characterized in cancer cachexia in humans and their therapeutic potential for muscle wasting.Recent findingsChanges in microRNAs in muscle of cancer patients have been demonstrated for the first time and these are associated with dysregulated signalling networks during muscle wasting. These data, together with studies in animal models, indicate that microRNAs are attractive therapeutic candidates for maintaining muscle mass, both during and following cancer treatment ultimately improving patient outcomes.SummaryCancer cachexia is a complex metabolic condition associated with muscle wasting. Maintenance of muscle mass in cancer patients can improve their response to therapy and prognosis. microRNAs, which can act as oncogenes or tumour suppressors, are also dysregulated in muscle of cachexia patients. Studies in animal models of muscle wasting have demonstrated that microRNAs regulate muscle mass and strength. With more microRNA-based therapeutics in clinical trials and first RNA drugs approved, microRNAs present an attractive novel therapeutic avenue for maintaining muscle homeostasis in cachexia patients to improve their prognosis

micro(RNA)-managing muscle wasting.

Progressive skeletal muscle wasting is a natural consequence of aging and is common in chronic and acute diseases. Loss of skeletal muscle mass and function (strength) often leads to frailty, decreased independence and increased risk of hospitalization. Despite progress made in our understanding of mechanisms underlying muscle wasting, there is still no treatment available, with exercise training and dietary supplementation improving, but not restoring muscle mass and/or function. There has been slow progress in developing novel therapies for muscle wasting, either during aging or disease, partially due to the complex nature of processes underlying muscle loss. The mechanisms of muscle wasting are multifactorial, with a combination of factors underlying age- and disease-related functional muscle decline. These factors include well characterized changes in muscle such as changes in protein turnover, and more recently described mechanisms such as autophagy or satellite cell senescence. Advances in transcriptomics and other high-throughput approaches have highlighted significant deregulation of skeletal muscle gene and protein levels during aging and disease. These changes are regulated at different levels, including post-transcriptional gene expression regulation by microRNAs. microRNAs, potent regulators of gene expression, modulate many processes in muscle, and microRNA-based interventions have been recently suggested as a promising new therapeutic strategy against alterations in muscle homeostasis. Here, we review recent developments in understanding the aging-associated mechanisms of muscle wasting and explore potential microRNA-based therapeutic avenues

The functional consequences of age-related changes in microRNA expression in skeletal muscle

A common characteristic of ageing is disrupted homeostasis between growth and atrophy of skeletal muscle resulting in loss of muscle mass and function, which is associated with sarcopenia. Sarcopenia is related to impaired balance, increased falls and decline in quality of life of older people. Ageing-related transcriptome and proteome changes in skeletal muscle have been characterised, however the molecular mechanisms underlying sarcopenia are still not fully understood. microRNAs are novel regulators of gene expression known to modulate skeletal muscle development and homeostasis. Expression of numerous microRNAs is disrupted in skeletal muscle with age however, the functional consequences of this are not yet understood. Given that a single microRNA can simultaneously affect multiple signalling pathways, microRNAs are potent modulators of pathophysiological changes occurring during ageing. Here we use microRNA and transcript expression profiling together with microRNA functional assays to show that disrupted microRNA:target interactions play an important role in maintaining muscle homeostasis. We identified miR-181a as a regulator of the sirtuin1 (Sirt1) gene expression in skeletal muscle and show that the expression of miR-181a and its target gene is disrupted in skeletal muscle from old mice. Moreover, we show that miR-181a:Sirt1 interactions regulate myotube size. Our results demonstrate that disrupted microRNA:target interactions are likely related to the pathophysiological changes occurring in skeletal muscle during ageing