title: Myosin light chain phosphorylation is critical for adaptation to cardiac stress.
abstract: BACKGROUND
  Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined.
  
  
  RESULTS
  We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40% and cMLCK levels by ≈85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems.
  
  
  CONCLUSIONS
  Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610-0274, USA.
authors.forename: Sonisha A
authors.initials: SA
authors.lastname: Warren
authors.forename: Laura E
authors.initials: LE
authors.lastname: Briggs
authors.forename: Huadong
authors.initials: H
authors.lastname: Zeng
authors.forename: Joyce
authors.initials: J
authors.lastname: Chuang
authors.forename: Eileen I
authors.initials: EI
authors.lastname: Chang
authors.forename: Ryota
authors.initials: R
authors.lastname: Terada
authors.forename: Moyi
authors.initials: M
authors.lastname: Li
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.forename: Stewart H
authors.initials: SH
authors.lastname: Lecker
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: Julie
authors.initials: J
authors.lastname: Maupin-Furlowe
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
authors.forename: Hideko
authors.initials: H
authors.lastname: Kasahara
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D017725:Ventricular Pressure / Q000502:physiology
chemical_list: D018994:Myosin Light Chains; D025801:Ubiquitin; C107184:myosin light chain 2; D009219:Myosin-Light-Chain Kinase; D046988:Proteasome Endopeptidase Complex; D024722:Cardiac Myosins