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Secreted miRNAs from primary myocytes

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder, characterized primarily by a progressive loss of motor neurons in whose degeneration skeletal muscle involvement has been demonstrated. Skeletal muscle is a plastic tissue that responds to insults through proliferation and differentiation of satellite cells. The process of skeletal muscle degeneration and regeneration are finely regulated by signals that regulate satellite cell proliferation and differentiation. It is known that satellite cell differentiation is impaired in ALS, but little is known about the involvement of miRNAs and their role in intercellular communication in skeletal muscle in ALS. Here we demonstrated impaired differentiation of satellite cells derived from ALS mice related to the impairment of myogenic p38MAPK and PKA/pCREB signaling pathways that can be regulated by miR-882 and -134-5p. These miRNAs participate in autocrine signaling in association with miR-26a-5p, that, secreted from WT and captured by ALS myoblasts, enhances ALS-related myoblast differentiation by repressing Smad4-related signals. These findings underscore the urgency of better understanding the role of intercellular communication and the molecular mechanisms underlying ALS pathogenesis and progression. They also suggest that miRNAs could be targeted as potential therapeutic agents to enhance myofiber regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE274702 | GEO | 2025/07/02

REPOSITORIES: GEO

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Project description:Background Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. To date, multiple panels of biomarkers have been described in ALS patients and murine models. Nevertheless, none of them has sufficient specificity and thus the molecular signature for ALS prognosis and progression remains to be fully elucidated. Circulating microRNAs (miRNAs) are highly stable molecules that are recently used as promising biomarkers for many types of human cancer and muscle disorders. Here we overcome this limitation through a longitudinal study, analyzing serum levels of circulating miRNAs in ALS patients during the progression of the pathology. Method We performed next-generation sequencing (NGS) analysis and absolute RT quantification of serum samples of 27 ALS patients and 11 healthy control; among them 13 ALS patients were studied every three months till the end of the disease. Results We demonstrated that miR-151a-3p, miR-206 and miR-199a-3p are significantly expressed at the mild, moderate and severe stages of ALS pathology, whereas the expression levels of miR-133a and miR-199a-5p remained low during the whole study and retain diagnostic significance in the moderate and severe stages (miR-133a) and in mild and terminal stages (miR-199a-5p) of the disease. Moreover, we analysed the miRNAs serum levels during the progression of the disease in each patient and we demonstrated that high levels of miR-206, miR-133a, miR-151a-5p, miR-151a-3p can predict a slower clinical decline of patient functionality suggesting that these miRNAs represent good potential prognostic markers for ALS disease. Conclusion This study is the first to perform a longitudinal absolute quantification of circulating miRNAs during ALS disease. We highlighted putative biomarkers for diagnosis, prognosis and disease stage identification of ALS patients providing cut-off threshold for most of the miRNAs analyzed. In addition, our results define a molecular signature of ALS phenotypes that could help to define appropriate enrollments of patients in clinical trials.

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.

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Secreted miRNAs from primary myocytes

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