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...

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Main Authors: Manfredi, Leandro Henrique, Ang, Joshur, Peker, Nesibe, Dagda, Ruben K., McFarlane, Craig
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/149016
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.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
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
Autophagy
G Protein-coupled Receptor Kinase 2
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
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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Manfredi, Leandro Henrique
Ang, Joshur
Peker, Nesibe
Dagda, Ruben K.
McFarlane, Craig
format Article
author Manfredi, Leandro Henrique
Ang, Joshur
Peker, Nesibe
Dagda, Ruben K.
McFarlane, Craig
author_sort Manfredi, Leandro Henrique
title 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_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_sort g protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells
publishDate 2021
url https://hdl.handle.net/10356/149016
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