Pyruvate dehydrogenase kinase 4 promotes ubiquitin–proteasome system‐dependent muscle atrophy

作者：Ibotombi Singh Sinam, Dipanjan Chanda, Themis Thoudam, Min‐Ji Kim, Byung‐Gyu Kim, Hyeon‐Ji Kang, Jung Yi Lee, Seung‐Hoon Baek, Shin‐Yoon Kim, Bum-Jin Shim, Dongryeol Ryu, Jae‐Han Jeon, In‐Kyu Lee · 发表于：Journal of Cachexia Sarcopenia and Muscle · 年份：2022 · DOI：10.1002/jcsm.13100 · 被引用次数：41 · 研究领域：Muscle Physiology and Disorders、Biochemical Acid Research Studies、Exercise and Physiological Responses

BACKGROUND: Muscle 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. METHODS: The 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. RESULTS: Knockdown 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 ch...