Sarcopenia and noncoding RNAs: A comprehensive review

Sarcopenia is an elderly disease and is related to frailty and loss of muscle mass (atrophy) of older adults. The exact molecular mechanisms contributing to the pathogenesis of disease are yet to be discovered. In recent years, the role of noncoding RNAs in the pathogenesis of almost every kind of malignant and nonmalignant conditions is pinpointed. Regarding their regulatory function, there have been an increased number of studies on the role of noncoding RNAs in the progress of sarcopenia. In this manuscript, we review the role of microRNAs and long noncoding RNAs in development and progression of disease. We also discuss their potential as therapeutic targets in this condition.

(miRNAs) and long noncoding RNAs (lncRNAs). miRNAs were first discovered about 30 years ago in Caenorhabditis elegans (Hammond, 2015). They are relatively small RNAs (22 nt) and in most cases they target 3′ UTR of related mRNAs and contribute to translation inhibition, although their interaction with other types of RNAs is also approved (O'brien et al., 2018). Because of their role in cell proliferation, apoptosis, and inflammation, dysregulation and certain mutations in miRNAs are related to different kinds of diseases, including cancer and nonmalignant conditions like sarcopenia (Ardekani & Naeini, 2010;Zheng et al., 2018).
Long noncoding RNAs (lncRNAs) are a type of RNA longer than 200 nt in length which are produced by RNA polymerase II (Jarroux et al., 2017). Based on their relationship with the nearby proteincoding gene, lncRNAs are classified as sense or antisense lncRNAs.
They are located in the nucleus, cytoplasm, body fluids, and even mitochondria (Fernandes et al., 2019) and act as imperative cis-or trans-regulators in numerous biological processes. These RNAs have different biological functions, including interaction with DNA, mRNA, miRNAs, and regulation of gene expression in multiple ways (X. Zhang et al., 2019). LncRNAs contribute to various epigenetic regulations via recruitment of chromatin remodeling complexes to particular genomic loci (Ma et al., 2012). Some other lncRNAs participate in gene expression regulation through interaction with protein partners. These lncRNAs are involved in imprinting, control of cell cycle control transition, alternative splicing, and modulation of chromatin structure (Ma et al., 2012). In addition, lncRNAs contribute to enhancer-regulating gene activation and function as interacting partners or precursors for short regulatory noncoding RNAs.
Recently, their involvement in different types of diseases, including sarcopenia is approved (Mikovic et al., 2018).
In this manuscript, we aim to present complete data of miRNAs and lncRNAs that are related to the pathogenesis of sarcopenia and F I G U R E 1 Muscle sarcopenia, cellular senescence, and mitochondrial dysfunction all interact with one another as humans grow. Oversized mitochondria are characterized by densely linked networks, an abnormal shape, decreased bioenergetic efficiency, and elevated ROS generation; these symptoms emerge in response to an imbalance in mitochondrial dynamics toward fusion. Caspase-3 degrades actomyosin complexes, resulting in protein fragments that are finally destroyed by the ubiquitin-proteasome system. Muscle protein breakdown and myonuclear death are triggered by the increased ROS production caused by mitochondrial fragmentation and the stimulation of fission. ATP, adenosine triphosphate; mtDNA, mitochondrial DNA; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype. similar conditions like muscle atrophy and muscle waste. For this purpose, we searched PubMed database with the key words "lncRNA" or "long non-coding RNA" and "sarcopenia," plus "micro-RNA" and "sarcopenia" and also "non-coding RNA" and "sarcopenia." Collected manuscripts were assessed to find the relevant data including features of samples and cell lines, signaling pathways, and related targets of miRNAs and lncRNAs.

| miRNAs in sarcopenia: animal studies
The majority of miRNA studies on sarcopenia and muscle atrophy have been conducted on animals, especially rodents and broilers. miR-133 and its subtypes are dysregulated in mice and rats. In mice, miR-133 has been shown to be downregulated in C57BL/6 mice and mice C2C12 cell line. Target genes of this miRNA are Musk, FOXO3, and sirt1. These genes are related to muscle degeneration and are inhibited by miR-133; therefore, downregulation of this miRNA results in muscle degeneration (Giakoumaki et al., 2022). On the other hand, different subtypes of miR-133, including miR-133b-3p, miR-133a-3p and miR-133c are upregulated in the serum of sarcopenic male Sprague-Dawley rats (W. . Expression of miR-133a is also upregulated in C57BL/6 mice and mice C2C12 cell line (Soriano-Arroquia, House, et al., 2016).
In the cluster of miR-let family, different subtypes of this miRNA are dysregulated. For instance, miR-Let-7d-3p is regulated by nuclear factor-κB (NF-κB) pathway ( Figure 2). Activation of this pathway contributes to the upregulation of miR-let-7d-3p, resulting in inhibition of HMGA2 and muscular stem cell proliferation in aged mice (Itokazu et al., 2022). In aged diabetic patients and C2C12 cells, upregulation of miR-let-7g-5p induces muscle atrophy through inflammation with the help of tumor necrosis factor-α/interleukin-6 (IL6) (Tsai et al., 2022).
In both BALB/C mice and Sprague-Dawley rats, two different subtypes of miR-486 are downregulated. Dexamethasone induces muscle atrophy, and in a group of BALB/C mice subjected to this drug, BMSCs exosomes containing miR-486-5p counteracted effects of the drug and inhibited muscular degeneration (Z. Li, Liu, et al., 2021). In another study on Sprague-Dawley rats, it has been found that miR-486 is downregulated in aged mice. miR-486 inhibits PTEN and promotes PI3K/AKT cascades, leading to reversal of skeletal muscle atrophy (Gao et al., 2021). miR-21 upregulation has been shown in aged C57Bl/6 mice. This miRNA expedites FOXO3 nuclear localization, which is an atrophy inducing transcription factor; therefore, upregulation of miR-21 reduces muscle viability and promotes muscle atrophy (Borja-Gonzalez et al., 2020). Also, in another expression analysis of sarcopenic male Sprague-Dawley rats, upregulation of miR-21-3p was approved (W. .  Abbreviations: CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease; DEX, dexamethasone.
| 1421 miR-143 expression has been shown to be reduced by using a computer visualization model in aged C57BL/6 mice and C2C12 cells.
In another study on 18 sarcopenic patients, downregulation of miR-486 has been shown. This miRNA directly targets pax7 and promotes myoblast differentiation. In addition, miR-486 activates the PI3K/AKT signaling pathway and contributes to cell proliferation .
Increased apoptosis of the muscle cells contributes to sarcopenia ( Figure 3). miR-532-3p has been shown to be under-expressed in GHAFOURI-FARD ET AL.
| 1425 sarcopenic patients. A poor diet could result in a decreased level of miR-532-3p and this miRNA targets BAK1, an apoptosis inducer. By inhibiting BAK1, miR-532-3p prevents apoptosis of the myocytes .
A set of myomiRs (muscle tissue-specific microRNAs) including miR-133a, miR-133b, miR-206, miR-208b, and miR-499 has been shown to be downregulated in sarcopenic patients. In fact, there is a direct link between muscle performance and circulating myomiRs, indicating that the altered levels of miRNAs could either prevent or promote sarcopenia (Valášková et al., 2021).

| Long noncoding RNAs and sarcopenia
LncRNA MAR1 has been shown to be downregulated in aged C57BL/ 6J mice. Identical to the majority of lncRNAs, MAR1 has a sponging activity. By sponging miR-487b, it regulates Wnt5a and facilitates muscle differentiation in mice. Upregulation of MAR1 could potentially help patients with sarcopenia and muscle atrophy (Z. K. Zhang et al., 2018).
LncRNA DLEU2 has been approved to be upregulated in sarcopenic patients. The mechanism of action is sponging miR-181a and inhibiting muscle regeneration by upregulating SEPP1. Since the expression of SEPP1 is lower in muscles compared to other tissues, it might have adverse effects on muscle growth .

MALAT1, a known lncRNA with different contributions in malignant
and nonmalignant conditions, is downregulated in aged C57BL/6 mice.
As the mice ages, MALAT1 reduction occurs. Activation of p53 during aging leads to miR-34a expression and a depletion of MALAT1 ultimately leads to muscle atrophy (Ruan et al., 2021).
Calcium level is an important factor in the function of myocytes.