β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility.
Date
2018-12-27
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Attention Stats
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.
Type
Department
Description
Provenance
Subjects
Citation
Permalink
Published Version (Please cite this version)
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.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
James William Wisler
Lan Mao
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.
Paul Brian Rosenberg
Howard Allan Rockman
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.
Robert J. Lefkowitz
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win.
Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. Dr. Lefkowitz began his research career in the late 1960’s and early 1970’s when there was not a clear consensus that specific receptors for drugs and hormones even existed. His group spent 15 difficult years developing techniques for labeling the receptors with radioactive drugs and then purifying the four different receptors that were known and thought to exist for adrenaline, so called adrenergic receptors. In 1986 Dr. Lefkowitz transformed the understanding of what had by then become known as G protein coupled receptors because of the way the receptor signal for the inside of a cell through G proteins, when he and his colleagues cloned the gene for the beta2-adrenergic receptor. They immediately recognized the similarity to a molecule called rhodopsin which is essentially a light receptor in the retina. This unexpected finding established the beta receptor and rhodopsin as the first member of a new family of proteins. Because each has a peptide structure, which weaves across the cell membrane seven times, these receptors are referred to as seven transmembrane receptors. This super family is now known to be the largest, most diverse and most therapeutically accessible of all the different kinds of cellular receptors. There are almost a thousand members of this receptor family and they regulate virtually all known physiological processes in humans. They include the receptors not only to numerous hormones and neurotransmitters but for the receptors which mediate the senses of sweet and bitter taste and smell amongst many others. Dr. Lefkowitz also discovered the mechanism by which receptor signaling is turned off, a process known as desensitization. Dr. Lefkowitz work was performed at the most fundamental and basic end of the research spectrum and has had remarkable consequences for clinical medicine. Today, more than half of all prescription drug sales are of drugs that target either directly or indirectly the receptors discovered by Dr. Lefkowitz and his trainees. These include amongst many others beta blockers, angiotensin receptor blockers or ARBs and antihistamines. Over the past decade he has discovered novel mechanisms by which the receptors function which may lead to the development of an entirely new class of drugs called “biased agonists”. Several such compounds are already in advanced stages of clinical testing. Dr. Lefkowitz has received numerous honors and awards, including the National Medal of Science, the Shaw Prize, the Albany Prize, and the 2012 Nobel Prize in Chemistry. He was elected to the USA National Academy of Sciences in 1988, the Institute of Medicine in 1994, and the American Academy of Arts and Sciences in 1988.
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.