title: Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease.
abstract: Actin-myosin interactions provide the driving force underlying each heartbeat. The current view is that actin-bound regulatory proteins play a dominant role in the activation of calcium-dependent cardiac muscle contraction. In contrast, the relevance and nature of regulation by myosin regulatory proteins (for example, myosin light chain-2 [MLC2]) in cardiac muscle remain poorly understood. By integrating gene-targeted mouse and computational models, we have identified an indispensable role for ventricular Mlc2 (Mlc2v) phosphorylation in regulating cardiac muscle contraction. Cardiac myosin cycling kinetics, which directly control actin-myosin interactions, were directly affected, but surprisingly, Mlc2v phosphorylation also fed back to cooperatively influence calcium-dependent activation of the thin filament. Loss of these mechanisms produced early defects in the rate of cardiac muscle twitch relaxation and ventricular torsion. Strikingly, these defects preceded the left ventricular dysfunction of heart disease and failure in a mouse model with nonphosphorylatable Mlc2v. Thus, there is a direct and early role for Mlc2 phosphorylation in regulating actin-myosin interactions in striated muscle contraction, and dephosphorylation of Mlc2 or loss of these mechanisms can play a critical role in heart failure.
authors.affiliation: Department of Medicine, UCSD, La Jolla, California 92093-0613C, USA. fasheikh@ucsd.edu
authors.forename: Farah
authors.initials: F
authors.lastname: Sheikh
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Campbell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Lyon
authors.forename: Joyce
authors.initials: J
authors.lastname: Chuang
authors.forename: Dan
authors.initials: D
authors.lastname: Fitzsimons
authors.forename: Jared
authors.initials: J
authors.lastname: Tangney
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Hidalgo
authors.forename: Charles S
authors.initials: CS
authors.lastname: Chung
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Hideko
authors.initials: H
authors.lastname: Kasahara
authors.forename: Majid
authors.initials: M
authors.lastname: Ghassemian
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Omens
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Henk L
authors.initials: HL
authors.lastname: Granzier
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000205:Actomyosin / Q000502:physiology; D000818:Animals; D001696:Biomechanical Phenomena; D020013:Calcium Signaling; D024722:Cardiac Myosins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology*; D007700:Kinetics; D051379:Mice; D008817:Mice, Mutant Strains; D008955:Models, Cardiovascular; D009126:Muscle Relaxation / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D018994:Myosin Light Chains / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D013329:Structure-Activity Relationship; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000503:physiopathology
chemical_list: D018994:Myosin Light Chains; C107184:myosin light chain 2; D010768:Phosphoserine; D000205:Actomyosin; D024722:Cardiac Myosins