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Long-term PGC1? overexpression leads to apoptosis, autophagy and muscle wasting.

ABSTRACT: Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1?) and its splice variant PGC1?4 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1?, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1? in the skeletal muscle, we have found that PGC1? progressively decreases skeletal muscle mass predominantly associated with loss of type 2b fast-twitch myofibers. Paradoxically, PGC1? represses the ubiquitin-proteolysis degradation pathway genes resulting in ubiquitinated protein accumulation in muscle. However, PGC1? overexpression triggers up-regulation of apoptosis and autophagy genes, resulting in robust activation of these cell degenerative processes, and a concomitant increase in muscle protein oxidation. Concurrently, PGC1? up-regulates apoptosis and/or autophagy transcriptional factors such as E2f1, Atf3, Stat1, and Stat3, which may be facilitating myopathy. Therefore, PGC1? activation negatively affects muscle mass over time, particularly fast-twitch muscles, which should be taken into consideration along with its known aerobic effects in the skeletal muscle.

SUBMITTER: Sopariwala DH

PROVIDER: S-EPMC5578977 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting.

Sopariwala Danesh H DH Yadav Vikas V Badin Pierre-Marie PM Likhite Neah N Sheth Megha M Lorca Sabina S Vila Isabelle K IK Kim Eun Ran ER Tong Qingchun Q Song Min Sup MS Rodney George G GG Narkar Vihang A VA

Scientific reports 20170831 1

Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1α) and its splice variant PGC1α4 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1β, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1β in the skeletal muscle, we have found that PGC1β progressively decreases ...[more]

PMID: 28860475

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Project description:BackgroundChronic kidney disease (CKD) is commonly associated with cachexia, a condition that causes skeletal muscle wasting and an unfavourable prognosis. Although mechanisms leading to cachexia have been intensively studied, the advance of biological knowledges and technologies encourages us to make progress in understanding the pathogenesis of this disorder. Long noncoding RNAs (lncRNAs) are defined as >200 nucleotides RNAs but lack the protein-coding potential. LncRNAs are involved in the pathogenesis of many diseases, but whether they functionally involve in muscle protein loss has not been investigated.MethodsWe performed lncRNA array and identified an lncRNA, which we named Atrolnc-1, remarkably elevated in atrophying muscles from mice with cachexia. We examined how overexpression or knockdown of Atrolnc-1 could influence muscle protein synthesis and degradation. We also examined whether inhibition of Atrolnc-1 ameliorates muscle wasting in mice with CKD.ResultsWe documented that Atrolnc-1 expression is continuously increased in muscles of mice with fasting (5.4 fold), cancer (2.0 fold), or CKD (5.1 fold). We found that depressed insulin signalling stimulates the transcription factor C/EBP-? binding to the promoter of Atrolnc-1 and promotes the expression of Atrolnc-1. In cultured C2C12 myotubes, overexpression of Atrolnc-1 increases protein degradation (0.45±0.03 vs. 0.64±0.02, *p<0.05); Atrolnc-1 knockdown significantly reduces the rate of protein degradation stimulated by serum depletion (0.61±0.03 vs. 0.47±0.02, *p<0.05). Using mass spectrometry and a lncRNA pull-down assay, we identified that Atrolnc-1 interacts with A20 binding inhibitor of NF-?B-1 (ABIN-1). The interaction impairs function, resulting in enhanced NF-?B activity plus MuRF-1 transcription. This response is counteracted by CRISPR/dCas9 mediated overexpression. In muscles from normal mice, overexpression of Atrolnc-1 stimulates a 2.7-fold increase in MuRF-1 expression leading to myofibers atrophy. In contrast, Atrolnc-1 knockdown attenuates muscle wasting by 42% in mice with CKD via suppression of NF-?B activity and MuRF-1 expression.ConclusionsOur findings provide evidence that lncRNAs initiates the pathophysiological process of muscle wasting. The interaction between Atrolnc-1 and NF-?B signalling modulates muscle mass and proteolysis in CKD and perhaps other catabolic conditions.

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Long-term PGC1? overexpression leads to apoptosis, autophagy and muscle wasting.

Publications

Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting.

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