β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility.

Abstract

BACKGROUND:β2-adrenergic receptors (β2ARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of β2AR stimulation on skeletal muscle is anabolic growth, which has led to the use of agonists such as clenbuterol by athletes to enhance muscle performance. While previous work has demonstrated that β2ARs can engage distinct signaling and functional cascades mediated by either G proteins or the multifunctional adaptor protein, β-arrestin, the precise role of β-arrestin in skeletal muscle physiology is not known. Here, we tested the hypothesis that agonist activation of the β2AR by clenbuterol would engage β-arrestin as a key transducer of anabolic skeletal muscle growth. METHODS:The contractile force of isolated extensor digitorum longus muscle (EDL) and calcium signaling in isolated flexor digitorum brevis (FDB) fibers were examined from the wild-type (WT) and β-arrestin 1 knockout mice (βarr1KO) followed by chronic administration of clenbuterol (1 mg/kg/d). Hypertrophic responses including fiber composition and fiber size were examined by immunohistochemical imaging. We performed a targeted phosphoproteomic analysis on clenbuterol stimulated primary cultured myoblasts from WT and βarr1KO mice. Statistical significance was determined by using a two-way analysis with Sidak's or Tukey's multiple comparison test and the Student's t test. RESULTS:Chronic administration of clenbuterol to WT mice enhanced the contractile force of EDL muscle and calcium signaling in isolated FDB fibers. In contrast, when administered to βarr1KO mice, the effect of clenbuterol on contractile force and calcium influx was blunted. While clenbuterol-induced hypertrophic responses were observed in WT mice, this response was abrogated in mice lacking β-arrestin 1. In primary cultured myoblasts, clenbuterol-stimulated phosphorylation of multiple pro-hypertrophy proteins required the presence of β-arrestin 1. CONCLUSIONS:We have identified a previously unappreciated role for β-arrestin 1 in mediating β2AR-stimulated skeletal muscle growth and strength. We propose these findings could have important implications in the design of future pharmacologic agents aimed at reversing pathological conditions associated with skeletal muscle wasting.

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Citation

Published Version (Please cite this version)

10.1186/s13395-018-0184-8

Publication Info

Kim, Jihee, Chad A Grotegut, James W Wisler, Tianyu Li, Lan Mao, Minyong Chen, Wei Chen, Paul B Rosenberg, et al. (2018). β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility. Skeletal muscle, 8(1). p. 39. 10.1186/s13395-018-0184-8 Retrieved from https://hdl.handle.net/10161/19481.

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Scholars@Duke

Wisler

James William Wisler

Assistant Professor of Medicine

Lan Mao

Assistant Professor Emeritus in Medicine

I. Research:
As the director of mouse physiology laboratory, in charge for the all events related with Dr. Howard Rockman's molecular biology laboratory studies needs.
Participate in research in rodents model:
Perform surgery and serve as co-investigator in studies on transgenic mice with heart failure. Develop models of hypertrophy in small animal using micro-surgical techniques (aortic constriction, left ventricular infarction and abdominal aortocaval fistula) and perform a variety physiological studies, obtain and analysis data on hemodynamic study and prepare tissue specimens for father molecular biological study.
Develop and apply surgical techniques for in vivo myocardial function study on small animal, such as, using new developed devices study in vivo mice cardiac function (pressure-volume lop), instrumented mice for conscious blood pressure measure or administration of medicine---carotid artery or gull duck catheterization, and conscious mice echocardiography.
Develop techniques for micro-injection of proteins and vectors in to mouse left ventricle, coronary artery and portal vein.


II. Teaching
10% of time allocated/spent---
Train postdoctoral fellows, visiting scientists and students from all over the world in laboratory procedure involving, including endotracheal intubations, cardiac catheterization, coronary occlusion and intrathoracic/intra-abdominal surgical procedures.
Teach methods of data recording and analysis using laboratory equipment and computer programs, echocardiography apply and measurement.


III. Consultant
Consult and teach microsurgical techniques related on small animals such as, rabbits, rat, hamsters and mice, like mice heart-lung transplantation, portal vein injection and mini-pump implant.
Co-laboratory with large range of Universities and Research Institutes from United States an other countries.

Rosenberg

Paul Brian Rosenberg

Professor of Medicine
Rockman

Howard Allan Rockman

Edward S. Orgain Distinguished Professor of Cardiology, in the School of Medicine

Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure

Overall Research Direction: The major focus of this laboratory is to understand the molecular mechanisms of hypertrophy and heart failure. My laboratory uses a strategy that combines state of the art molecular techniques to generate transgenic and gene targeted mouse models, combined with sophisticated physiologic measures of in vivo cardiac function. In this manner, candidate molecules are either selectively overexpressed in the mouse heart or genes ablated followed by an in-depth analysis of the physiological phenotype. To model human cardiac disease, we have created several models of cardiac overload in the mouse using both microsurgical techniques and genetic models of cardiac dysfunction.

Areas of Research
1) Signaling: G protein-coupled receptor signaling in hypertrophy and heart failure focusing on the concept of biased signaling of 7 transmembrane receptors.

2) Molecular physiology: In depth physiological analysis of cardiac function in genetically altered mice to understand the role of G protein-coupled receptor signaling pathways on the development of heart failure in vivo.


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