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Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading.

ABSTRACT: Reversing established muscle atrophy following mechanical unloading is of great clinical challenge. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in myogenesis. Here we identified a lncRNA (mechanical unloading-induced muscle atrophy-related lncRNA [lncMUMA]) enriched in muscle, which was the most downregulated lncRNA during muscle atrophy development in hindlimb suspension (HLS) mice. The in vitro and in vivo data demonstrated that the decreased expression levels of lncMUMA closely associated with a reduction of myogenesis during mechanical unloading. Mechanistically, lncMUMA promoted myogenic differentiation by functioning as a miR-762 sponge to regulate the core myogenic regulator MyoD in vitro. The enforced expression of lncMUMA relieved the decreases in MyoD protein and muscle mass in miR-762 knockin mice. Therapeutically, the enforced expression of lncMUMA improved the in vitro myogenic differentiation of myoblasts under microgravity simulation, prevented the muscle atrophy development, and reversed the established muscle atrophy in HLS mice. These findings identify lncMUMA as an anabolic regulator to reverse established muscle atrophy following mechanical unloading.

SUBMITTER: Zhang ZK

PROVIDER: S-EPMC6225098 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading.

Zhang Zong-Kang ZK Li Jie J Guan Daogang D Liang Chao C Zhuo Zhenjian Z Liu Jin J Lu Aiping A Zhang Ge G Zhang Bao-Ting BT

Molecular therapy : the journal of the American Society of Gene Therapy 20181025 11

Reversing established muscle atrophy following mechanical unloading is of great clinical challenge. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in myogenesis. Here we identified a lncRNA (mechanical unloading-induced muscle atrophy-related lncRNA [lncMUMA]) enriched in muscle, which was the most downregulated lncRNA during muscle atrophy development in hindlimb suspension (HLS) mice. The in vitro and in vivo data demonstrated that the decreased expression levels ...[more]

PMID: 30415659

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Project description:BackgroundWeightlessness-induced skeletal muscle atrophy, accompanied by complex biochemical and physiological changes, has potentially damaged consequences. However, there is still an insufficient effective strategy to treat skeletal muscle atrophy. Therefore, exploring the molecular mechanisms regulating skeletal muscle atrophy and effective protection is necessary.MethodsRNA sequencing (RNA-seq) analysis was used to detect differentially expressed genes (DEGs) in the soleus muscle at 12, 24, 36 hours, three days, and seven days after hindlimb unloading in rats. Pearson correlation heatmaps and principal component analysis (PCA) were applied to analyze DEGs' expression profiles. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for cluster analysis of DEGs. Ingenuity pathway analysis (IPA) was used to analyze specific biological processes further.ResultsAt different time points (12, 24, 36 hours, three days, seven days) after hindlimb unloading, the expression levels of 712, 1,109, 1,433, 1,162, and 1,182 genes in rat soleus muscle were upregulated, respectively, whereas the expression levels of 1,186, 1,324, 1,632, 1,446, and 1,596 genes were downregulated, respectively. PCA revealed that rat soleus muscle showed three different transcriptional phases within seven days after hindlimb unloading. KEGG and GO annotation indicated that the first transcriptional phase primarily involved the activation of stress responses, including oxidative stress, and the inhibition of cell proliferation and angiogenesis; the second transcriptional phase primarily involved the activation of proteolytic systems and, to a certain degree, inflammatory responses; and the third transcriptional phase primarily involved extensive activation of the proteolytic system, significant inhibition of energy metabolism, and activation of the aging process and slow-to-fast muscle conversion.ConclusionsDifferent physiological processes in rat skeletal muscles were activated sequentially after unloading. From these activated biological processes, the three transcriptional phases after skeletal muscle unloading can be successively defined as the stress response phase, the atrophic initiation phase, and the atrophic phase. Our study not only helps in the understanding of the molecular mechanisms underlying weightlessness-induced muscle atrophy but may also provide an important time window for the treatment and prevention of weightlessness-induced muscle atrophy.

Project description:BackgroundLong-term exposure to microgravity will cause skeletal muscle atrophy, which can cause serious harm to astronauts in space travel. Therefore, it is important to explore skeletal muscle atrophy's molecular mechanism for its prevention and treatment. However, as an important regulatory approach of skeletal muscle physiology, the role of alternative splicing in skeletal muscle atrophy, especially skeletal muscle atrophy caused by disuse, is unclear.MethodsWe established a rat hindlimb unloading model and performed RNA sequencing on soleus muscle, which was seriously atrophied during unloading. Several bioinformatics methods were used to identify alternative splicing events and determine their gene functions.ResultsMany alternative splicing events were found to occur at different time points (12 h, 24 h, 36 h, 3 days, and 7 days) after hindlimb unloading. These differential alternative splicing events mainly occurred in the gene's coding domain sequence region, and 59% of the alternative splicing events caused open reading frameshift. Bioinformatics analysis results showed that genes with different alternative splicing events were enriched in multiple pathways related to muscle atrophy, including the insulin signaling pathway, endocytosis, mitophagy, and ubiquitin-proteasome pathway. Moreover, alternative splicing of several deubiquitinase genes persisted during skeletal muscle atrophy induced by unloading. Additionally, we identified 10 differentially expressed RNA binding proteins during skeletal muscle atrophy induced by unloading, mainly containing Xpo4, Eif4e2, P4ha1, Lrrfip1, Zc3h14, Emg1, Hnrnp h1, Mbnl2, RBfox1, and Mbnl1. Hnrnp h1 and Mbnl2 were significantly downregulated, and RBfox1 and Mbnl1 were significantly upregulated during skeletal muscle atrophy caused by unloading.ConclusionsTo the best of our knowledge, the present study is the first to propose alternative splicing alterations related to disuse-induced muscle atrophy, emphasizing that alternative splicing is a new focus of attention in the occurrence of muscle atrophy.

Project description:Long noncoding RNA (lncRNA) is a crucial factor in the progression of insulin resistance (IR). Resveratrol (RSV) exhibits promising therapeutic potential for IR. However, there are few studies on whether RSV improves IR through lncRNA. This study aimed to determine whether RSV could influence the expression of lncRNA and to elucidate the underlying mechanism. Mice were divided into three groups: control group, high-fat diet (HFD) group, and HFD + RSV group. We conducted a high-throughput sequencing analysis to detect lncRNA and mRNA expression signatures and the ceRNA-network in the skeletal muscles of mice that were fed an HFD to induce IR. Hierarchical clustering, gene enrichment, and gene ceRNA-network analyses were subsequently conducted. Differentially expressed lncRNAs were selected and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The biological functions of the selected lncRNAs were investigated by silencing the target genes via lentivirus transfection of C2C12 mouse myotube cells. RSV treatment reversed the expression of 338 mRNAs and 629 lncRNAs in the skeletal muscles of mice with HFD-induced IR. The results of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database analyses indicated that the differentially expressed mRNAs modulated type II diabetes mellitus. After validating randomly selected lncRNAs via RT-qPCR, we identified a novel lncRNA, NONMMUT044897.2, which was upregulated in the HFD group and reversed with RSV treatment. Additionally, NONMMUT044897.2 was proven to function as a ceRNA of microRNA- (miR-) 7051-5p. Suppressor of Cytokine Signaling 1 (SOCS1) was confirmed as a target of miR-7051-5p. We further performed lentivirus transfection to knock down NONMMUT044897.2 in vitro and found that NONMMUT044897.2 silenced SOCS1 and potentiated the insulin signaling pathway. Hence, RSV mimicked the silencing effect of lentivirus transfection on NONMMUT044897.2. Our study revealed that RSV reduced IR in mouse skeletal muscles via the regulation of NONMMUT044897.2.

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Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading.

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Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading.

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