α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway
| Autor: | Xingcai Cai, Pingwen Xu, Liao Zhengrui, Yaqiong Xu, Songbo Wang, Gang Shu, Yongliang Zhang, Xiaotong Zhu, Qing-Yan Jiang, Canjun Zhu, Yexian Yuan, Lulu Yu, Lina Wang, Ping Gao, Kongping Xing |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Duchenne muscular dystrophy Metabolite Muscle Fibers Skeletal Procollagen-Proline Dioxygenase Muscle Proteins Protein degradation Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound Endurance training Internal medicine Genetics medicine Animals Muscle Skeletal Molecular Biology Protein Stability Chemistry Research Skeletal muscle medicine.disease Muscle atrophy Mice Inbred C57BL Muscular Dystrophy Duchenne Citric acid cycle Disease Models Animal Muscular Atrophy 030104 developmental biology medicine.anatomical_structure Endocrinology Proteolysis Mice Inbred mdx Ketoglutaric Acids Receptors Adrenergic beta-2 medicine.symptom Corticosterone ITGA7 Metabolic Networks and Pathways Biotechnology |
| Zdroj: | The FASEB Journal. 32:488-499 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.201700670r |
| Popis: | Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. α-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3), one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the β2 adrenergic receptor (ADRB2) as a downstream target for PHD3. We found AKG inhibited PHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise-generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.—Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., Shu, G. α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway. |
| Databáze: | OpenAIRE |
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