title: Acute heart failure with cardiomyocyte atrophy induced in adult mice by ablation of cardiac myosin light chain kinase.
abstract: Under pressure overload, initial adaptive hypertrophy of the heart is followed by cardiomyocyte elongation, reduced contractile force, and failure. The mechanisms governing the transition to failure are not fully understood. Pressure overload reduced cardiac myosin light chain kinase (cMLCK) by ∼80% within 1 week and persists. Knockdown of cMLCK in cardiomyocytes resulted in reduced cardiac contractility and sarcomere disorganization. Thus, we hypothesized that acute reduction of cMLCK may be causative for reduced contractility and cardiomyocyte remodelling during the transition from compensated to decompensated cardiac hypertrophy.
  
  
  
  To mimic acute cMLCK reduction in adult hearts, the floxed-Mylk3 gene that encodes cMLCK was inducibly ablated in Mylk3(flox/flox)/merCremer mice (Mylk3-KO), and compared with two control mice (Mylk3(flox/flox) and Mylk3(+/+)/merCremer) following tamoxifen injection (50 mg/kg/day, 2 consecutive days). In Mylk3-KO mice, reduction of cMLCK protein was evident by 4 days, with a decline to below the level of detection by 6 days. By 7 days, these mice exhibited heart failure, with reduction of fractional shortening compared with those in two control groups (19.8 vs. 28.0% and 27.7%). Severely convoluted cardiomyocytes with sarcomeric disorganization, wavy fibres, and cell death were demonstrated in Mylk3-KO mice. The cardiomyocytes were also unable to thicken adaptively to pressure overload.
  
  
  
  Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Massengill
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA.
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Ashraf
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA.
authors.forename: Rajib R
authors.initials: RR
authors.lastname: Chowdhury
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Chrzanowski
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA.
authors.forename: Jeena
authors.initials: J
authors.lastname: Kar
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA.
authors.forename: Sonisha A
authors.initials: SA
authors.lastname: Warren
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Walter
authors.affiliation: Advanced Magnetic Resonance Imaging and Spectroscopy Facility, University of Florida, Gainesville, FL, USA.
authors.forename: Huadong
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Electron Microscopy and Bio-imaging Laboratory, University of Florida, Gainesville, FL, USA.
authors.forename: Byung-Ho
authors.initials: BH
authors.lastname: Kang
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Rd, M543, Gainesville, FL 32610-0274, USA hkasahar@ufl.edu.
authors.forename: Hideko
authors.initials: H
authors.lastname: Kasahara
mesh_terms: D000208:Acute Disease; D000222:Adaptation, Physiological; D000818:Animals; D001284:Atrophy; D020013:Calcium Signaling; D024722:Cardiac Myosins / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D012518:Sarcomeres / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D018994:Myosin Light Chains; C107184:myosin light chain 2; D009219:Myosin-Light-Chain Kinase; C000613996:cardiac myosin light chain kinase, mouse; D024722:Cardiac Myosins
keywords: Heart failure; Inducible knockout; Kinase