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The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells.

ABSTRACT: Adult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice lacking the crucial proteasomal component, Rpt3. Ablation of Rpt3 in satellite cells decreased proteasome activity. Proteasome dysfunction in Rpt3-deficient satellite cells impaired their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. We found that inactivation of proteasomal activity induced proliferation defects and apoptosis in satellite cells. Mechanistically, insufficient proteasomal activity upregulated the p53 pathway, which caused cell-cycle arrest. Our findings delineate a critical function of the proteasome system in maintaining satellite cells in adult muscle.

SUBMITTER: Kitajima Y

PROVIDER: S-EPMC6294073 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells.

Kitajima Yasuo Y Suzuki Naoki N Nunomiya Aki A Osana Shion S Yoshioka Kiyoshi K Tashiro Yoshitaka Y Takahashi Ryosuke R Ono Yusuke Y Aoki Masashi M Nagatomi Ryoichi R

Stem cell reports 20181108 6

Adult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice ...[more]

PMID: 30416048

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Project description:BackgroundMuscle atrophy, leading to muscular dysfunction and weakness, is an adverse outcome of sustained period of glucocorticoids usage. However, the molecular mechanism underlying this detrimental condition is currently unclear. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscle and has been implicated in the pathogenesis of several diseases. The current study was designed to investigated and delineate the role of PDK4 in the context of muscle atrophy, which could be identified as a potential therapeutic avenue to protect against dexamethasone-induced muscle wasting.MethodsThe dexamethasone-induced muscle atrophy in C2C12 myotubes was evaluated at the molecular level by expression of key genes and proteins involved in myogenesis, using immunoblotting and qPCR analyses. Muscle dysfunction was studied in vivo in wild-type and PDK4 knockout mice treated with dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, muscle weight and muscle histology were assessed. The expression of myogenesis markers were analysed using qPCR, immunoblotting and immunoprecipitation. The study was extended to in vitro human skeletal muscle atrophy analysis.ResultsKnockdown of PDK4 was found to prevent glucocorticoid-induced muscle atrophy and dysfunction in C2C12 myotubes, which was indicated by induction of myogenin (0.3271 ± 0.102 vs 2.163 ± 0.192, ****P < 0.0001) and myosin heavy chain (0.3901 ± 0.047 vs. 0.7222 ± 0.082, **P < 0.01) protein levels and reduction of muscle atrophy F-box (10.77 ± 2.674 vs. 1.518 ± 0.172, **P < 0.01) expression. In dexamethasone-induced muscle atrophy model, mice with genetic ablation of PDK4 revealed increased muscle strength (162.1 ± 22.75 vs. 200.1 ± 37.09 g, ***P < 0.001) and muscle fibres (54.20 ± 11.85% vs. 84.07 ± 28.41%, ****P < 0.0001). To explore the mechanism, we performed coimmunoprecipitation and liquid chromatography-mass spectrometry analysis and found that myogenin is novel substrate of PDK4. PDK4 phosphorylates myogenin at S43/T57 amino acid residues, which facilitates the recruitment of muscle atrophy F-box to myogenin and leads to its subsequent ubiquitination and degradation. Finally, overexpression of non-phosphorylatable myogenin mutant using intramuscular injection prevented dexamethasone-induced muscle atrophy and preserved muscle fibres.ConclusionsWe have demonstrated that PDK4 mediates dexamethasone-induced skeletal muscle atrophy. Mechanistically, PDK4 phosphorylates and degrades myogenin via recruitment of E3 ubiquitin ligase, muscle atrophy F-box. Rescue of muscle regeneration by genetic ablation of PDK4 or overexpression of non-phosphorylatable myogenin mutant indicates PDK4 as an amenable therapeutic target in muscle atrophy.

Dataset Information

The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells.

Publications

The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells.

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