G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells
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 increa...
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2021
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/149016 |
| _version_ | 1826113687088267264 |
|---|---|
| author | Manfredi, Leandro Henrique Ang, Joshur Peker, Nesibe Dagda, Ruben K. McFarlane, Craig |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Manfredi, Leandro Henrique Ang, Joshur Peker, Nesibe Dagda, Ruben K. McFarlane, Craig |
| author_sort | Manfredi, Leandro Henrique |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T03:27:18Z |
| format | Journal Article |
| id | ntu-10356/149016 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:27:18Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1490162023-02-28T16:57:25Z G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells Manfredi, Leandro Henrique Ang, Joshur Peker, Nesibe Dagda, Ruben K. McFarlane, Craig School of Biological Sciences Science::Biological sciences Autophagy G Protein-coupled Receptor Kinase 2 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. 2021-05-11T02:29:56Z 2021-05-11T02:29:56Z 2019 Journal Article Manfredi, L. H., Ang, J., Peker, N., Dagda, R. K. & McFarlane, C. (2019). G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells. American Journal of Physiology: Cell Physiology, 317(4), C674-C686. https://dx.doi.org/10.1152/ajpcell.00516.2018 0363-6143 https://hdl.handle.net/10356/149016 10.1152/ajpcell.00516.2018 31268780 2-s2.0-85072509662 4 317 C674 C686 en American Journal of Physiology: Cell Physiology © 2019 the American Physiological Society. Licensed under Creative Commons Attribution CC-BY 4.0. application/pdf |
| spellingShingle | Science::Biological sciences Autophagy G Protein-coupled Receptor Kinase 2 Manfredi, Leandro Henrique Ang, Joshur Peker, Nesibe Dagda, Ruben K. McFarlane, Craig G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells |
| title | G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells |
| title_full | G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells |
| title_fullStr | G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells |
| title_full_unstemmed | G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells |
| title_short | G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells |
| title_sort | g protein coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin mediated autophagy in muscle cells |
| topic | Science::Biological sciences Autophagy G Protein-coupled Receptor Kinase 2 |
| url | https://hdl.handle.net/10356/149016 |
| work_keys_str_mv | AT manfredileandrohenrique gproteincoupledreceptorkinase2regulatesmitochondrialbioenergeticsandimpairsmyostatinmediatedautophagyinmusclecells AT angjoshur gproteincoupledreceptorkinase2regulatesmitochondrialbioenergeticsandimpairsmyostatinmediatedautophagyinmusclecells AT pekernesibe gproteincoupledreceptorkinase2regulatesmitochondrialbioenergeticsandimpairsmyostatinmediatedautophagyinmusclecells AT dagdarubenk gproteincoupledreceptorkinase2regulatesmitochondrialbioenergeticsandimpairsmyostatinmediatedautophagyinmusclecells AT mcfarlanecraig gproteincoupledreceptorkinase2regulatesmitochondrialbioenergeticsandimpairsmyostatinmediatedautophagyinmusclecells |