G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells
| Autor: | Ruben K. Dagda, Nesibe Peker, Joshur Ang, L. H. Manfredi, Craig McFarlane |
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| Přispěvatelé: | School of Biological Sciences |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
autophagy G-Protein-Coupled Receptor Kinase 2 Physiology GRK2 Myostatin Mitochondrion Myoblasts Mice 03 medical and health sciences 0302 clinical medicine Receptors Adrenergic beta Myokine Autophagy medicine Animals Myocyte Respiratory function Muscle Skeletal Muscle Cells G protein-coupled receptor kinase biology Chemistry G Protein-coupled Receptor Kinase 2 Biological sciences [Science] Skeletal muscle Cell Biology musculoskeletal system Mitochondria Cell biology 030104 developmental biology medicine.anatomical_structure Mitochondrial biogenesis biology.protein myoblast Receptors Adrenergic beta-2 030217 neurology & neurosurgery Research Article Signal Transduction |
| Zdroj: | American Journal of Physiology-Cell Physiology |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00516.2018 |
| Popis: | G protein-coupled receptor kinase 2 (GRK2) is an important protein involved in β-adrenergic receptor desensitization. In addition, studies have shown GRK2 can modulate different metabolic processes in the cell. For instance, GRK2 has been recently shown to promote mitochondrial biogenesis and increase ATP production. However, the role of GRK2 in skeletal muscle and the signaling mechanisms that regulate GRK2 remain poorly understood. Myostatin is a well-known myokine that has been shown to impair mitochondria function. Here, we have assessed the role of myostatin in regulating GRK2 and the subsequent downstream effect of myostatin regulation of GRK2 on mitochondrial respiration in skeletal muscle. Myostatin treatment promoted the loss of GRK2 protein in myoblasts and myotubes in a time- and dose-dependent manner, which we suggest was through enhanced ubiquitin-mediated protein loss, as treatment with proteasome inhibitors partially rescued myostatin-mediated loss of GRK2 protein. To evaluate the effects of GRK2 on mitochondrial respiration, we generated stable myoblast lines that overexpress GRK2. Stable overexpression of GRK2 resulted in increased mitochondrial content and enhanced mitochondrial/oxidative respiration. Interestingly, although overexpression of GRK2 was unable to prevent myostatin-mediated impairment of mitochondrial respiratory function, elevated levels of GRK2 blocked the increased autophagic flux observed following treatment with myostatin. Overall, our data suggest a novel role for GRK2 in regulating mitochondria mass and mitochondrial respiration in skeletal muscle. Agency for Science, Technology and Research (A*STAR) Published version This study was funded by the Agency for Science, Technology, and Research (A*STAR), Singapore and partially funded by NIH Grants GM103554 and NS105783-01 (to R. K. Dagda). We are also indebted to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (5662-13-3), Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Fundação de Amparo a` Pesquisa do Estado de São Paulo, Brazil, for financial support. |
| Databáze: | OpenAIRE |
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