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The β-arrestin-biased β-adrenergic receptor blocker carvedilol enhances skeletal muscle contractility
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2020
-
Abstract
- A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a β(2)-adrenergic receptor (β(2)AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in β-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of β(2)AR agonists. Carvedilol, classically defined as a βAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a β-arrestin-biased ligand for the β(2)AR, stimulating β-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via β-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other β-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by β-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with βAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.
- Subjects :
- 0301 basic medicine
Agonist
Male
medicine.medical_specialty
Adrenergic receptor
medicine.drug_class
Adrenergic beta-Antagonists
030204 cardiovascular system & hematology
Muscle hypertrophy
Contractility
03 medical and health sciences
Mice
0302 clinical medicine
Internal medicine
medicine
Arrestin
Animals
Muscle, Skeletal
Carvedilol
Mice, Knockout
Multidisciplinary
business.industry
Skeletal muscle
Biological Sciences
medicine.disease
030104 developmental biology
Endocrinology
medicine.anatomical_structure
beta-Arrestin 1
Sarcopenia
Female
business
medicine.drug
Muscle Contraction
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 117
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....66107c88774b3a61471debe598474553