The biology of ageing and the omics revolution

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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

Micro(RNA)-managing muscle wasting (vol 127, pg 619, 2019)

In the first sentence of ACKNOWLEDGMENTS, the incorrect author was credited with producing Fig. 1. The correct sentence should read: "A. Soriano-Arroquia produced the figure using Affinity Designer version 1.6.4 (http://affinity.serif.com/en-gb/designer/).

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

myomiR-dependent switching of BAF60 variant incorporation into Brg1 chromatin remodeling complexes during embryo myogenesis

Myogenesis involves the stable commitment of progenitor cells followed by the execution of myogenic differentiation, processes that are coordinated by myogenic regulatory factors, microRNAs and BAF chromatin remodeling complexes. BAF60a, BAF60b and BAF60c are structural subunits of the BAF complex that bind to the core ATPase Brg1 to provide functional specificity. BAF60c is essential for myogenesis; however, the mechanisms regulating the subunit composition of BAF/Brg1 complexes, in particular the incorporation of different BAF60 variants, are not understood. Here we reveal their dynamic expression during embryo myogenesis and uncover the concerted negative regulation of BAF60a and BAF60b by the muscle-specific microRNAs (myomiRs) miR-133 and miR-1/206 during somite differentiation. MicroRNA inhibition in chick embryos leads to increased BAF60a or BAF60b levels, a concomitant switch in BAF/Brg1 subunit composition and delayed myogenesis. The phenotypes are mimicked by sustained BAF60a or BAF60b expression and are rescued by morpholino knockdown of BAF60a or BAF60b. This suggests that myomiRs contribute to select BAF60c for incorporation into the Brg1 complex by specifically targeting the alternative variants BAF60a and BAF60b during embryo myogenesis, and reveals that interactions between tissue-specific non-coding RNAs and chromatin remodeling factors confer robustness to mesodermal lineage determination

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