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MiR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle

ABSTRACT: MicroRNAs (miRNAs) are critical regulators of skeletal muscle development and adaptation, orchestrating the balance between proliferation, differentiation, and tissue repair. Here, we identify miR-339-5p as a previously unrecognized, conserved regulator of skeletal muscle remodeling. Transcriptomic analysis from human, mouse, and rat studies revealed that miR-339-5p is consistently upregulated in skeletal muscle under conditions of stress or injury and declines during myogenic differentiation in vitro. Gain-of-function experiments demonstrated that miR-339-5p overexpression impairs expression of genes associated with myogenic differentiation and promotes expression of proliferative markers in both primary human myotubes and mouse C2C12 cells. Transcriptomic profiling confirmed widespread repression of pathways involved in cytoskeletal organization, myofibrillar assembly, and mitochondrial function. In vivo, electroporation-mediated overexpression of miR-339-5p in mouse tibialis anterior altered regeneration-associated gene expression and increased the number of immature fibers, therefore modulating tissue remodeling during post-injury growth. Integrated analyses combining target prediction algorithms, differentiation-associated correlations, and overexpression datasets identified seven conserved high-confidence miR-339-5p targets, among which the autophagy-associated phosphatase MTMR3 emerged as the most consistently regulated candidate. Collectively, our data demonstrate that miR-339-5p functions as a conserved inhibitor of myogenic progression, linking injury-induced stress responses to delayed differentiation and altered muscle remodeling. These findings establish miR-339-5p as a potential therapeutic target in conditions characterized by impaired muscle regeneration or dysregulated tissue remodeling.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE327356 | GEO | 2026/06/16

REPOSITORIES: GEO

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			Action	DRS
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	GSE327356_counts_human.csv.gz	Csv
	GSE327356_counts_mouse.csv.gz	Csv

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Project description:MicroRNAs (miRNAs) are important in the regulation of many biological processes including muscle development. However, little is known regarding miRNA regulation of muscle regeneration. In mature murine tibialis anterior muscle following injury, 298 miRNAs were significantly changed during the time course of muscle regeneration including 86 that were altered greater than 10-fold as compared to uninjured muscle. Temporal miRNA expression patterns were identified and included inflammation-related miRNAs (miR-223 and -147) that increased immediately after injury; this pattern contrasted to that of mature muscle-specific miRNAs (miR-1, -133a and -499) that were abruptly decreased following injury and then up-regulated in later regenerative events. Another cluster of miRNAs were transiently increased in the early days of muscle regeneration. This included miR-351, a miRNA that was also transiently expressed during myogenic progenitor cell (MPC) differentiation in vitro. Based on computational predictions, further studies demonstrated that E2f3 was a target of miR-351 in myoblasts. Moreover, knockdown of miR-351 expression inhibited MPC proliferation and promoted apoptosis during MPC differentiation, whereas miR-351 overexpression protected MPC from apoptosis during differentiation. Collectively, these observations suggest that miR-351 is involved in both the maintenance of MPC proliferation and the transition of MPC into differentiated myotubes. Thus, a novel, time-dependent sequence of molecular events during skeletal muscle regeneration has been identified, i.e., miR-351 inhibits E2f3 expression, a key regulator of cell cycle progression and proliferation, and promotes MPC proliferation and protects early differentiating MPC from apoptosis, important events in the hostile tissue environment after acute muscle injury. Skeletal muscles are damaged and repaired repeatedly throughout life. Muscle regeneration maintains locomotor function during aging and delays the appearance of clinical symptoms in neuromuscular diseases, such as Duchenne muscular dystrophy. The capacity for skeletal muscle growth and regeneration is conferred by satellite cells located between the basal lamina and the sarcolemma of mature myofibers. Upon injury, satellite cells reenter the cell cycle, proliferate, and then exit the cell cycle either to renew the quiescent satellite cell pool or to differentiate into mature myofibers. Despite recent advances, genes involved in these processes are still largely unknown. Understanding the molecular mechanisms that regulate satellite cell activities could promote development of novel countermeasures to enhance muscle regeneration that is compromised by diseases or aging. Using a muscle injury mouse model, we profiled miRNA expression during muscle regeneration.

Project description:Background: Heart failure characterized by reduced ejection fraction (HFrEF) is characterized by impaired cardiac function, with myocardial remodeling being a key pathological change in its progression. Plasma exosomal microRNAs(miRNAs) are promising non-invasive biomarkers with potential applications in the early prevention and treatment of HFrEF. Materials and methods: We used high-throughput miRNA sequencing to analyze plasma exosomes from 5 patients with heart failure with reduced ejection fraction (HFrEF) and 5 healthy volunteers to identify differentially expressed miRNAs. The miRanda program, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and WikiPathways were used for target gene prediction and pathway analysis. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR), the expression of exosomal miRNAs was verified in plasma samples from 40 patients with HFrEF and 40 healthy controls. Differential ventricular remodeling miRNAs and target genes predicted by miRanda were verified by qRT-PCR (n=40). Results: In comparison to healthy controls, high-throughput sequencing of the plasma exosomes of HFrEF patients showed that 10 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated. qRT-PCR validation confirmed that hsa-miR-22-5p, hsa-miR-181b-5p, and hsa-miR-339-5p were significantly upregulated (P < 0.05), while hsa-miR-192-5p (P < 0.05) and hsa-miR-1469 (P < 0.01) were significantly downregulated. No significant difference was observed for hsa-miR-320a-3p (P > 0.05). According to bioinformatics studies, hsa-miR-339-5p regulates the PI3K/AKT signaling pathway to target NOD-like receptor family CARD domain-containing 5 (NLRC5), impacting myocardial remodeling. The plasma levels of NLRC5 were lower in the HFrEF group than in the control group (P＜0.01), whereas the mRNA levels of PI3K and AKT were higher in the HFrEF group than in the control group (P＜0.01). Conclusion: This study highlights the distinct manifestation of plasma exosomal miRNAs in HFrEF and confirms the function of hsa-miR-339-5p in promoting ventricular remodeling through NLRC5. Potential as a treatment target for HFrEF has been demonstrated by hsa-miR-339-5p, providing new directions for future treatment strategies.

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MiR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle

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