Myosin regulatory light chain phosphorylation attenuates cardiac hypertrophy.
Hyperphosphorylation of myosin regulatory light chain (RLC) in cardiac muscle is proposed to cause compensatory hypertrophy. We therefore investigated potential mechanisms in genetically modified mice. Transgenic (TG) mice were generated to overexpress Ca2+/calmodulin-dependent myosin light chain kinase specifically in cardiomyocytes. Phosphorylation of sarcomeric cardiac RLC and cytoplasmic nonmuscle RLC increased markedly in hearts from TG mice compared with hearts from wild-type (WT) mice. Quantitative measures of RLC phosphorylation revealed no spatial gradients. No significant hypertrophy or structural abnormalities were observed up to 6 months of age in hearts of TG mice compared with WT animals. Hearts and cardiomyocytes from WT animals subjected to voluntary running exercise and isoproterenol treatment showed hypertrophic cardiac responses, but the responses for TG mice were attenuated. Additional biochemical measurements indicated that overexpression of the Ca2+/calmodulin-binding kinase did not perturb other Ca2+/calmodulin-dependent processes involving Ca2+/calmodulin-dependent protein kinase II or the protein phosphatase calcineurin. Thus, increased myosin RLC phosphorylation per se does not cause cardiac hypertrophy and probably inhibits physiological and pathophysiological hypertrophy by contributing to enhanced contractile performance and efficiency.
Huang
Jian
J
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Shelton
John M
JM
Richardson
James A
JA
Kamm
Kristine E
KE
Stull
James T
JT
D000367:Age Factors; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010805:Physical Conditioning, Animal; D011817:Rabbits; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D002316:Cardiotonic Agents; D018994:Myosin Light Chains; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009219:Myosin-Light-Chain Kinase; D019703:Calcineurin; D007545:Isoproterenol