title: Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy.
abstract: GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease. In this study we generated a novel skeletal muscle-specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2fl/fl) to gain a better understanding of the role of GRK2 in skeletal muscle physiology. In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the specific force of contraction of the fast-twitch extensor digitorum longus muscle yet had no effect on the slow-twitch soleus muscle. Despite these effects in isolated muscle, exercise capacity was not altered in MLC-Cre:GRK2fl/flmice compared with wild-type controls. Skeletal muscle hypertrophy stimulated by clenbuterol, a β2-adrenergic receptor (β2AR) agonist, was significantly enhanced in MLC-Cre:GRK2fl/flmice; mechanistically, this seems to be due to increased clenbuterol-stimulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle. In summary, our study provides the first insights into the role of GRK2 in skeletal muscle physiology and points to a role for GRK2 as a modulator of contractile properties in skeletal muscle as well as β2AR-induced hypertrophy.
authors: From the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140-4106.
authors: Benjamin P
authors: BP
authors: Woodall
authors: From the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140-4106.
authors: Meryl C
authors: MC
authors: Woodall
authors: From the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140-4106.
authors: Timothy S
authors: TS
authors: Luongo
authors: From the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140-4106.
authors: Laurel A
authors: LA
authors: Grisanti
authors: From the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140-4106.
authors: Douglas G
authors: DG
authors: Tilley
authors: From the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140-4106.
authors: John W
authors: JW
authors: Elrod
authors: From the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140-4106 walter.koch@temple.edu.
authors: Walter J
authors: WJ
authors: Koch
mesh_terms: D000818:Animals; D002976:Clenbuterol / Q000009:adverse effects* / Q000493:pharmacokinetics; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects* / Q000235:genetics; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D018343:Receptors, Adrenergic, beta-2; D051057:Proto-Oncogene Proteins c-akt; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D002976:Clenbuterol
keywords: Akt PKB; G protein-coupled receptor (GPCR); adrenergic receptor; mouse; muscle hypertrophy; muscle physiology