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RNA molecules are produced in the cell nucleus by transcription machinery that reads gene sequences from the genome. MicroRNAs are among the varieties of RNA molecule that are not translated by a ribosome to produce proteins. Instead they directly participate in cell functions, often by altering the expression of other genes. Many microRNAs appear to be important players in the regulation of specific cell behaviors and tissue functions, such as regeneration and maintenance of tissues.
In today’s open access paper, the authors provide an overview of some of the microRNAs that have been identified as important or potentially interesting in the context of the aging of muscle tissue, particularly in the decline of maintenance and regeneration. In the broader context beyond muscle tissue, a few first therapies that target specific microRNAs are making their way towards the clinic, primarily to treat forms of cancer. A broader range of such therapies is a possibility for the years ahead, including those aimed at restored muscle function in later life.
The role of non-coding RNAs in muscle aging: regulatory mechanisms and therapeutic potential
Non-coding RNAs (ncRNAs) are a varied family of RNA that do not code for proteins but are crucial for many biological activities, including gene regulation, epigenetic modifications, and chromatin remodeling. This class of RNAs includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and others. Non-coding RNAs have emerged as critical players in the regulation of various cellular processes, including those governing muscle tissue. In the context of muscle aging, research has uncovered a wealth of information about the roles ncRNAs play in mediating muscle loss, muscle regeneration, and overall muscle maintenance. For instance, modulating these miRNAs, such as miR-29, miR-143, and miR-431, could potentially improve age-related muscle regeneration.
In 2016, miR-501-3p was identified as a muscle-specific miRNA enriched in activated myogenic progenitor cells during muscle regeneration. Subsequent research demonstrated that miR-501 knockout mice exhibited a significant reduction in the diameter of newly formed myofibers. This result is a result of miR-501 controlling the expression of the sarcomeric gene via the estrogen-related receptor gamma (Esrrg). Another noteworthy miRNA, miR-7a-1, has been identified as highly expressed in aged muscle and as a downstream factor of HuR and Msi2. This miRNA plays a role in inhibiting the translation of Cry2 and modulating Muscle Stem cell (MuSC) differentiation. These findings contribute to our understanding of how miRNAs are involved in muscle regeneration and the aging process.
Some miRNAs, known as senescence-associated miRNAs, are identified that differentially expressed during cellular senescence contribute to its establishment and maintenance. For instance, miR-24 has been found to be downregulated in ex vivo MuSCs and regenerating muscle during aging. miR-24 regulates the generation of mitochondrial ROS through Prxd6 and subsequently influences MuSCs viability, myogenic potential and senescence. Modulating miR-24 in aged mouse are preserve satellite cells viability and mitochondria function.
Sarcopenia, characterized by age-related muscle loss, is influenced by various factors, with increased expression of E3 ligases like MuRF1 and Atrogin-1 in aged muscles, highlighting their involvement in the ubiquitin-proteasome system. Recent research has identified specific miRNAs associated with sarcopenia that target or modulate these E3 ligases, underscoring their importance in maintaining muscle. Notably, miRNAs located within the Dlk1-Dio3 cluster have induced hypertrophic phenotypes in myotubes. Among these miRNAs, including miR-376c, miR-668, miR-1197, miR-495, miR-377, miR-379, and miR-431, they directly bind to the 3′UTR of Atrogin-1, leading to the suppression of Atrogin-1 in both human and mouse muscle cells. Furthermore, miR-376c has shown remarkable potential in ameliorating skeletal muscle atrophy and improving muscle function in old mice. These miRNAs consistently exhibit downregulation in aged human muscles.
Recent studies have reported on the regulation of mitochondrial homeostasis controlling muscle mass. It was shown that miR-181a is crucial in controlling the age-related alteration of mitochondrial dynamics in muscle via targeting p62 and Park2. In vivo restoration of miR-181a levels in the muscles of old mice inhibited the accumulation of p62, Park2, and DJ-1 while maintaining mitochondrial content. In the end, this enhanced the size and force of myofibers. Collectively, these results indicate that miR-181a functions as an effective mitochondrial dynamics regulator, both in vitro and in vivo.