Abnormal contractile activity and calcium cycling in cardiac myocytes isolated from DMPK knockout mice.
Dysfunction of the gene encoding DMPK (myotonic dystrophy protein kinase) has been implicated in the human neuromuscular disease myotonic dystrophy (DM1). The cardiac features of the disease include progressive conduction defects and ventricular arrhythmias. These defects have been observed in hearts of mice deficient for DMPK function. We have investigated the role of DMPK in the function of ventricular cardiomyocytes using dmpk knockout (KO) mice. A deficit in DMPK caused enhanced basal contractility of single cardiomyocytes and an associated increase in intracellular Ca(2+), measured using fura-2. Biochemical measurements indicated hyperphosphorylation of phospholamban (PLB) in KO mice. This suggests increased Ca(2+) uptake into the sarcoplasmic reticulum (SR) as the underlying cause of enhanced contractility. This conclusion was supported by the larger amplitude of caffeine-induced Ca(2+) release from the SR in KO cardiomyocytes. Concurrent with hyperphosphorylated PLB, the response to isoprenaline was reduced. These observations suggest dmpk has a modulatory role in the control of intracellular Ca(2+) concentration in mouse ventricular cardiomyocytes, loss of which may contribute to cardiac dysfunction in DM1.
Pall
Gurman S
GS
Division of Molecular Genetics, Faculty of Biomedical and Life Sciences, Anderson College, University of Glasgow, Scotland, United Kingdom. g.pall@clinmed.gla.ac.uk
Johnson
Keith J
KJ
Smith
Godfrey L
GL
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D006321:Heart / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000032:analysis / Q000737:chemistry; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009223:Myotonic Dystrophy / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D065636:Myotonin-Protein Kinase; D009929:Organ Size / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics
C585517:DMPK protein, human; C585516:DMPK protein, mouse; D009124:Muscle Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D007545:Isoproterenol; D002118:Calcium