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MiRNAs discovered in serum of young, old, and disuse atrophy model. (A) Distribution of the miRNAs expressed in serum according to their sequence counts in young, old, and disuse atrophy model. The y-axis indicates the number of miRNAs with sequence read counts within the given range in the x-axis. (B) Top 10 known miRNAs expressed in serum of young, old, and disuse atrophy model, which constitute nearly 80% of all miRNAs expressed in the serum.
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Age-associated loss of muscle mass and function is a major cause of morbidity and mortality in the elderly adults. Muscular atrophy can also be induced by disuse associated with long-term bed rest or disease. Although miRNAs regulate muscle growth, regeneration, and aging, their potential role in acute muscle atrophy is poorly understood. Furthermo...
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... the serum samples, we identified a total of 287 known miRNAs after removal of low-abundance miRNAs with a wide dynamic range of read counts, from 10 to over 100,000 reads per million (Figure 2A). About 7% of these miRNAs had a copy number greater than 10,000 and about 80% a copy number less than 1,000. ...
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... 7% of these miRNAs had a copy number greater than 10,000 and about 80% a copy number less than 1,000. The normalized read count for each miRNA indicated that miR-486-5p was the most abundant miRNA detected in serum of young, old, and disuse atrophy model mice ( Figure 2B). The top 10 miRNAs by read count comprised approximately 80% of all sequence reads. ...
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... the serum samples, we identified a total of 287 known miR- NAs after removal of low-abundance miRNAs with a wide dynamic range of read counts, from 10 to over 100,000 reads per million (Figure 2A). About 7% of these miRNAs had a copy number greater than 10,000 and about 80% a copy number less than 1,000. ...
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... 7% of these miRNAs had a copy number greater than 10,000 and about 80% a copy number less than 1,000. The normalized read count for each miRNA indicated that miR-486-5p was the most abundant miRNA detected in serum of young, old, and disuse atrophy model mice ( Figure 2B). The top 10 miRNAs by read count comprised approximately 80% of all sequence reads. ...
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By the sixth decade of life, nearly one quarter of the population has substantial muscle atrophy, or sarcopenia. Despite the creation of a standardized definition of sarcopenia by the European Working Group on Sarcopenia in Older People, variability may exist in the diagnostic criteria utilized for clinical sarcopenia research. The primary objectiv...
Citations
... As LAMs are characterized by CD9 expression, we also confirmed that LAM-derived EVs contain CD9 ( Supplementary Fig. 1g). Finally, we examined the effect of age on miR-6236 expression by analyzing legacy small RNA-seq data from the serum of young (6 months) or aged (24 months) mice 17 . Consistent with secretion in EVs, miR-6236 was detected in the serum of these mice, but its levels were not significantly different between young and aged mice (Supplementary Fig. 1h). ...
Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.
... miRNAs play a pivotal role in sarcopenia as they regulate satellite cell quiescence and renewal, the function of the IGF-1/PI3K/Akt pathway, mitochondrial function, and fat infiltration in muscles [71,103]. Various miRNAs have shown to increase or decrease in muscles and blood in sarcopenia [104][105][106][107]. Moreover, overexpression of different miRNAs has been demonstrated to affect sarcopenia in either a positive or negative way, depending on studied miRNAs in in vitro or in vivo models [106,107]. ...
... Various miRNAs have shown to increase or decrease in muscles and blood in sarcopenia [104][105][106][107]. Moreover, overexpression of different miRNAs has been demonstrated to affect sarcopenia in either a positive or negative way, depending on studied miRNAs in in vitro or in vivo models [106,107]. Therefore, miRNAs are claimed to be potential biomarkers and targets of gene therapy for sarcopenia [108]. ...
Sarcopenia is a skeletal muscle disorder characterized by progressive and generalized decline in muscle mass and function. Although it is mostly known as an age-related disorder, it can also occur secondary to systemic diseases such as malignancy or organ failure. It has demonstrated a significant relationship with adverse outcomes, e.g., falls, disabilities, and even mortality. Several breakthroughs have been made to find a pharmaceutical therapy for sarcopenia over the years, and some have come up with promising findings. Yet still no drug has been approved for its treatment. The key factor that makes finding an effective pharmacotherapy so challenging is the general paradigm of standalone/single diseases, traditionally adopted in medicine. Today, it is well known that sarcopenia is a complex disorder caused by multiple factors, e.g., imbalance in protein turnover, satellite cell and mitochondrial dysfunction, hormonal changes, low-grade inflammation, senescence, anorexia of aging, and behavioral factors such as low physical activity. Therefore, pharmaceuticals, either alone or combined, that exhibit multiple actions on these factors simultaneously will likely be the drug of choice to manage sarcopenia. Among various drug options explored throughout the years, testosterone still has the most cumulated evidence regarding its effects on muscle health and its safety. A mas receptor agonist, BIO101, stands out as a recent promising pharmaceutical. In addition to the conventional strategies (i.e., nutritional support and physical exercise), therapeutics with multiple targets of action or combination of multiple therapeutics with different targets/modes of action appear to promise greater benefit for the prevention and treatment of sarcopenia
... In the realm of muscle atrophy regulation, research has unveiled a spectrum of miRNAs implicated in this intricate process. Notable examples include miR-455-3p, let-7d-3p, and miR-376c-3p, among others, which exert regulatory control over muscle quality in the context of aging [10][11][12] . Similarly, miR-424-5p, miR-542-3p/5p, and their counterparts have been associated with the modulation of muscle quality as it pertains to the progression of chronic obstructive pulmonary disease 13,14 . ...
MicroRNAs (miRNAs) may play a crucial regulatory role in the process of muscle atrophy induced by high-altitude hypoxia and its amelioration through resistance training. However, research in this aspect is still lacking. Therefore, this study aimed to employ miRNA microarray analysis to investigate the expression profile of miRNAs in skeletal muscle from an animal model of hypoxia-induced muscle atrophy and resistance training aimed at mitigating muscle atrophy. The study utilized a simulated hypoxic environment (oxygen concentration at 11.2%) to induce muscle atrophy and established a rat model of resistance training using ladder climbing, with a total intervention period of 4 weeks. The miRNA expression profile revealed 9 differentially expressed miRNAs influenced by hypoxia (e.g., miR-341, miR-32-5p, miR-465-5p) and 14 differentially expressed miRNAs influenced by resistance training under hypoxic conditions (e.g., miR-338-5p, miR-203a-3p, miR-92b-3p) (∣Fold Change∣≥1.5, p༜0.05). The differentially expressed miRNAs were found to target genes involved in muscle protein synthesis and degradation (such as Utrn, mdm2, eIF4E), biological processes (such as negative regulation of transcription from RNA polymerase II promoter, regulation of transcription, DNA-dependent), and signaling pathways (such as Wnt signaling pathway, MAPK signaling pathway, ubiquitin-mediated proteolysis, mTOR signaling pathway). This study provides a foundation for understanding and further exploring the molecular mechanisms underlying hypoxia-induced muscle atrophy and the mitigation of atrophy through resistance training.
... MiR-434 is a rodentspecific miRNA (miRBase, accessed on 9 September 2022). Although Jovičić et al. [28] showed that miR-434 is specifically expressed in rat cortical neurons, a few studies have also detected miR-434-3p in the skeletal muscle of rats and mice [51][52][53]. In neurons, miR-434-3p is suggested to be involved in regulating stress-induced transcripts [54]. ...
Traumatic brain injury (TBI) causes 10–20% of structural epilepsies and 5% of all epilepsies. The lack of prognostic biomarkers for post-traumatic epilepsy (PTE) is a major obstacle to the development of anti-epileptogenic treatments. Previous studies revealed TBI-induced alterations in blood microRNA (miRNA) levels, and patients with epilepsy exhibit dysregulation of blood miRNAs. We hypothesized that acutely altered plasma miRNAs could serve as prognostic biomarkers for brain damage severity and the development of PTE. To investigate this, epileptogenesis was induced in adult male Sprague Dawley rats by lateral fluid-percussion-induced TBI. Epilepsy was defined as the occurrence of at least one unprovoked seizure during continuous 1-month video-electroencephalography monitoring in the sixth post-TBI month. Cortical pathology was analyzed by magnetic resonance imaging on day 2 (D2), D7, and D21, and by histology 6 months post-TBI. Small RNA sequencing was performed from tail-vein plasma samples on D2 and D9 after TBI (n = 16, 7 with and 9 without epilepsy) or sham operation (n = 4). The most promising miRNA biomarker candidates were validated by droplet digital polymerase chain reaction in a validation cohort of 115 rats (8 naïve, 17 sham, and 90 TBI rats [21 with epilepsy]). These included 7 brain-enriched plasma miRNAs (miR-434-3p, miR-9a-3p, miR-136-3p, miR-323-3p, miR-124-3p, miR-212-3p, and miR-132-3p) that were upregulated on D2 post-TBI (p < 0.001 for all compared with naïve rats). The acute post-TBI plasma miRNA profile did not predict the subsequent development of PTE or PTE severity. Plasma miRNA levels, however, predicted the cortical pathology severity on D2 (Spearman ρ = 0.345–0.582, p < 0.001), D9 (ρ = 0.287–0.522, p < 0.001–0.01), D21 (ρ = 0.269–0.581, p < 0.001–0.05) and at 6 months post-TBI (ρ = 0.230–0.433, p < 0.001–0.05). We found that the levels of 6 of 7 miRNAs also reflected mild brain injury caused by the craniotomy during sham operation (ROC AUC 0.76–0.96, p < 0.001–0.05). In conclusion, our findings revealed that increased levels of neuronally enriched miRNAs in the blood circulation after TBI reflect the extent of cortical injury in the brain but do not predict PTE development.
... These post-transcriptional regulators are associated with multiple diseases and physiological conditions like aging (de Lencastre et al., 2010). Recently, an alteration in the expression of a significant number of miRNAs was identified during skeletal muscle mass dysfunction in elderly patients Jung et al., 2017). Changes in miRNA expression in muscle during aging in mice have also been reported , suggesting that these molecules may regulate critical cellular processes in the muscular decline associated with age. ...
Osteosarcopenic obesity (OSO) has been associated with increase immobility, falls, fractures, and other dysfunctions, which could increase mortality risk during aging. However, its etiology remains unknown. Recent studies revealed that sedentarism, fat gain, and epigenetic regulators are critical in its development. One effective intervention to prevent and treat OSO is exercise. Therefore, in the present study, by keeping rats in conditions of sedentarism and others under a low-intensity exercise routine, we established an experimental model of OSO. We determined the degree of sarcopenia, obesity, and osteopenia at different ages and analyzed the miRNA expression during the lifespan using miRNA microarrays from gastrocnemius muscle. Interestingly microarrays results showed that there is a set of miRNAs that changed their expression with exercise. The pathway enrichment analysis showed that these miRNAs are strongly associated with immune regulation. Further inflammatory profiles with IL-6/IL-10 and TNF-α/IL-10 ratios showed that exercised rats presented a lower pro-inflammatory profile than sedentary rats. Also, the body fat gain in the sedentary group increased the inflammatory profile, ultimately leading to muscle dysfunction. Exercise prevented strength loss over time and maintained skeletal muscle functionality over time. Differential expression of miRNAs suggests that they might participate in this process by regulating the inflammatory response associated with aging, thus preventing the development of OSO.
... Interestingly, not only the expression of miR-483-3p was seen differentially modulated under sarcopenic or cachectic conditions, but also many other miRNAs, such as miR-532, miR-155, miR-378, and miR-451a [114,115,130,156,163,168,169]. miRNA analysis of abdominal subcutaneous adipose tissue from cachectic patients revealed that the increase in miR-378 levels was linked to an increase in lipolysis, targeting hormone-sensitive lipase (LIPE), patatin-like phospholipase domain-containing protein 2 (PNPLA2), and PLIN1, while in muscle samples of sarcopenic old men, the downregulation was linked to an increase in muscle wasting due to the loss of muscle homeostasis [163,170]. ...
... Since it also plays a critical role in erythrocyte maturation, it is speculated that increased circulatory levels of miR-451a observed in sarcopenic patients could reflect a compensatory mechanism to induce erythroid maturation, resulting in an increased delivery of oxygen to muscles [169]. Lastly, the expression of miR-155 was found to be upregulated in muscle but downregulated in plasma samples of sarcopenic patients [130,168]. At the same time, Wu et al. demonstrated that breast cancer cell-secreted miR-155 promotes catabolism in resident adipocytes by downregulating the PPAR-γ expression. ...
Significant loss of muscle mass may occur in cachexia and sarcopenia, which are major causes of mortality and disability. Cachexia represents a complex multi-organ syndrome associated with cancer and chronic diseases. It is often characterized by body weight loss, inflammation, and muscle and adipose wasting. Progressive muscle loss is also a hallmark of healthy aging, which is emerging worldwide as a main demographic trend. A great challenge for the health care systems is the age-related decline in functionality which threatens the independence and quality of life of elderly people. This biological decline can also be associated with functional muscle loss, known as sarcopenia. Previous studies have shown that microRNAs (miRNAs) play pivotal roles in the development and progression of muscle wasting in both cachexia and sarcopenia. These small non-coding RNAs, often carried in extracellular vesicles, inhibit translation by targeting messenger RNAs, therefore representing potent epigenetic modulators. The molecular mechanisms behind cachexia and sarcopenia, including the expression of specific miRNAs, share common and distinctive trends. The aim of the present review is to compile recent evidence about shared and divergent epigenetic mechanisms, particularly focusing on miRNAs, between cachexia and sarcopenia to understand a facet in the underlying muscle wasting associated with these morbidities and disclose potential therapeutic interventions.
... rno-miR-434-5p is associated with aging and plays an important role in skeletal muscle metabolism [15]. Reportedly, the rno-miR-434-5p gene can be used as a biomarker of muscle damage because this gene is associated with muscle loss [16]. A recent study revealed that rno-miR-34c-5p is associated with neuronal nitric oxide synthase and causes muscle loss [17]. ...
As the geriatric population and life expectancy increase, the interest in preventing geriatric diseases, such as sarcopenia, is increasing. However, the causes of sarcopenia are unclear, and current diagnostic methods for sarcopenia are unreliable. We hypothesized that the changes in the expression of certain miRNAs may be associated with the pathophysiology of sarcopenia. Herein, we analyzed the miRNA expression profiles in the blood of young (3-months-old) healthy rats, old sarcopenic (17-months-old) rats, and age-matched (17-months-old) control rats. The changes in miRNA expression levels were analyzed using Bowtie 2 software. A total of 523 miRNAs were detected in the rat serum. Using scatter plots and clustering heatmap data, we found 130 miRNAs that were differentially expressed in sarcopenic rats (>2-fold change) compared to the expression in young healthy and age-matched control rats. With a threshold of >5-fold change, we identified 14 upregulated miRNAs, including rno-miR-133b-3p, rno-miR-133a-3p, rno-miR-133c, rno-miR-208a-3p, and rno-miR434-5p among others in the serum of sarcopenic rats. A protein network map based on these 14 miRNAs identified the genes involved in skeletal muscle differentiation, among which Notch1, Egr2, and Myocd represented major nodes. The data obtained in this study are potentially useful for the early diagnosis of sarcopenia and for the identification of novel therapeutic targets for the treatment and/or prevention of sarcopenia.
... miRNA can inhibit the expression of target genes in two ways by organizing mRNA translation or causing it to be explained by RISC [22,23]. In previous studies, it was found that miRNAs are involved in various regulatory pathways in skeletal muscle [24][25][26][27][28][29][30]. For example, miR-696 has been confirmed to be a physical-activity-dependent miRNA. ...
As it is well known, muscle atrophy is a process in which protein degradation increases and protein synthesis decreases. This process is regulated by a variety of links. Among them, microRNAs play an essential role in this process, which has attracted widespread attention. In this paper, we find that miR-27b-3p and Cbl-b genes are significantly differentially expressed in the induced atrophy model. The dual-luciferase experiment and Western blot analysis confirmed that miR-27b-3p could regulate the expression of Cbl-b. In C2C12-differentiated myotubes, the overexpression of the Cbl-b gene showed that Cbl-b could upregulate the expression of MuRF-1 and Atrogin-1, which are related marker genes of muscle atrophy, at both the mRNA and protein levels, indicating that the Cbl-b gene can specifically affect muscle atrophy. The knockdown of the Cbl-b gene after C2C12-differentiated myotubes induced atrophy treatment can downregulate the expression of muscle-atrophy-related genes, indicating that manual intervention to downregulate the expression of Cbl-b has a certain alleviating effect on muscle atrophy. These data suggest that miR-27b-3p can regulate the expression of the Cbl-b gene and then exert a particular influence on muscle atrophy through the Cbl-b gene.
... Several studies have identified miRNAs and lncRNAs implicated in sarcopenia [60][61][62]67,68]. The expression profiles of non-coding RNAs are altered in sarcopenia during skeletal muscle aging [62,[69][70][71][72][73][74][75]. Profiling studies on the expression levels of non-coding RNAs during sarcopenia induced by other diseases, such as cancer, have also been conducted [76][77][78][79][80]. Herein, we summarize the information regarding sarcopenia-induced expression of miRNAs and lncRNAs reported so far (Table 1). ...
... Profiling studies on the expression levels of non-coding RNAs during sarcopenia induced by other diseases, such as cancer, have also been conducted [76][77][78][79][80]. Herein, we summarize the information regarding sarcopenia-induced expression of miRNAs and lncRNAs reported so far (Table 1). miRNA Mouse Mouse quadriceps muscle young (aged 12 months, n = 24) and old (aged 24 months, n = 24) [70] Mouse gastrocnemius muscle young (aged 6 months, n = 6) and old (aged 24 months, n = 6) [72] Mouse tibialis anterior muscle young (aged 6 months, n = 3) and old (aged 24 months, n = 3) [74] Mouse tibialis anterior muscle and serum young (aged 6 months, n = 5) and old (aged 24 months, n = 5), and mice with disuse-induced atrophy (aged 6 months, n = 5) [71] Mouse gastrocnemius muscle young (aged 3 months, n = 20) and old (aged 26 months, n = 24) [73] Mouse quadriceps muscle young (aged 3 months, n = 6), and old (aged 28 months, n = 11) [63] Mouse gastrocnemius muscle OVX and sham group (aged 2 months and left for 15 weeks to induce sarcopenia) [77] Human Human skeletal muscle young (aged 31 years, n = 19) and old (aged 73 years, n = 17) [69] Human skeletal muscle cachectic (n = 22) and non-cachectic cancer (n = 20) patients [78] Human vastus lateralis muscle NSCLC patients with cachexia (n = 8), and healthy controls (n = 8) [80] LncRNA Mouse Mouse gastrocnemius muscle young (aged 6 months, n = 3) and old (aged 24 months, n = 3) [75] Mouse quadriceps muscle chronic kidney disease (CKD), starvation (STV), and cancer [79] Rat Rat femur and quadriceps muscle OVX and sham group (aged 6 months and left over for 12 weeks to induce sarcopenia, n = 12) ...
... In particular, eight of the downregulated miRNAs were located in a cluster at the imprinted Dlk1-Dio3 locus on chromosome 12 [72]. miRNAs expressed in the tibialis anterior muscle of young (aged 6 months) and aged (aged 24 months) mice were profiled using microarray and NGS [71,74]. Soriano-Arroquia et al., found that the expression of 16 miRNAs was downregulated, while that of 14 miRNAs was upregulated in the muscle during aging using a microarray [74]. ...
Sarcopenia is an age-related pathological process characterized by loss of muscle mass and function, which consequently affects the quality of life of the elderly. There is growing evidence that non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a key role in skeletal muscle physiology. Alterations in the expression levels of miRNAs and lncRNAs contribute to muscle atrophy and sarcopenia by regulating various signaling pathways. This review summarizes the recent findings regarding non-coding RNAs associated with sarcopenia and provides an overview of sarcopenia pathogenesis promoted by multiple non-coding RNA-mediated signaling pathways. In addition, we discuss the impact of exercise on the expression patterns of non-coding RNAs involved in sarcopenia. Identifying non-coding RNAs associated with sarcopenia and understanding the molecular mechanisms that regulate skeletal muscle dysfunction during aging will provide new insights to develop potential treatment strategies.
... Micro RNAs (miRs) are small non-coding RNAs, 21-23 nucleotides in length and regulate gene transcription by repressing translation and/or degrading mRNAs [5]. Several reports recognize an essential role of miRs in skeletal muscle health and disease, as aberrant expression of miRs is associated with multiple skeletal muscle diseases including sarcopenia [5,6]. miRs derived from skeletal muscle and other tissues are easily detectable in circulation, indicating their diagnostic potential in sarcopenia. ...
... miRs derived from skeletal muscle and other tissues are easily detectable in circulation, indicating their diagnostic potential in sarcopenia. Several studies indicate an altered expression of both the muscle-specific and non-muscle specific miRs in the circulation in the elderly [5,6]. Additionally, the patients with CHF also show significant alterations in the plasma miRs profile [7]. ...
... For example, miR-434-3p had the highest AUC on the ROC curve but performed relatively poorly in diagnosing loss of muscle mass, strength, and physical capacity. miR-434-3p is importantly expressed in both the cardiac and skeletal muscle and has a pathological role in both tissues [6,26]. For example, the expression of miR-434-3p is increased in the failing heart in heart diseases [26]. ...
Background:
Sarcopenia is a critical finding in patients with chronic heart failure (CHF). However, the search for a definitive biomarker to predict muscle and functional decline in CHF remains elusive.
Objectives:
We aimed to correlate the circulating levels of selected miRs with the indexes of sarcopenia during healthy aging and in patients with CHF.
Methods:
We analyzed the association of circulating microRNAs (miRs) levels including miR-21, miR-434-3p, miR424-5p, miR-133a, miR-455-3p and miR-181a with sarcopenia indexes in male, 61-73 years old healthy controls and patients with CHF (N = 89-92/group).
Results:
Patients with CHF had lower hand-grip strength (HGS), appendicular skeletal mass index (ASMI) and physical capacity than healthy controls. Circulating miR-21 levels were higher and miR-181a, miR-133a, miR-434-3p and miR-455-3p levels were lower in patients with CHF than healthy controls. Among the sarcopenia indexes, HGS showed the strongest correlation with miR-133a while ASMI showed the strongest correlations with miR-133a, miR-434-3p and miR-455-3p. Among the miRs, miR-434-3p showed the highest area under the curve in testing for sensitivity and specificity for CHF. These changes were associated with higher expressions of the markers of inflammation, oxidative stress and muscle damage in CHF patients.
Conclusion:
Taken together, our data show that circulating miRs can be useful markers of muscle health and physical capacity in the sarcopenic elderly with CHF.
