Physiol. Genomics Journal of Applied Physiology
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Physiol. Genomics (February 20, 2003). doi:10.1152/physiolgenomics.00107.2002
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Submitted on August 16, 2002
Accepted on February 17, 2003

Abnormal contractile activity and calcium cycling in cardiac myocytes isolated from dmpk KO mice

Gurman S Pall1*, Keith J Johnson2, and Godfrey L Smith3

1 Division of Molecular Genetics, University of Glasgow, Glasgow, United Kingdom; Division of Neuroscience and Biomedical Systems, University of Glasgow, Glasgow, United Kingdom; Pathology, University of Glasgow, Glasgow, United Kingdom
2 Division of Molecular Genetics, University of Glasgow, Glasgow, United Kingdom
3 Division of Neuroscience and Biomedical Systems, University of Glasgow, Glasgow, United Kingdom

* To whom correspondence should be addressed. E-mail: g.pall{at}clinmed.gla.ac.uk.

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 KO mice. A deficit in DMPK caused enhanced basal contractility of single cardiomyocytes and an associated increase in intracellular calcium (Ca2+), measured using Fura-2. Biochemical measurements indicated hyperphosphorylation of phospholamban (PLB) in KO mice. This suggests increased Ca2+ uptake into the sarcoplasmic reticulum (SR) as the underlying cause of enhanced contractility. This conclusion was supported by the larger amplitude of caffeine-induced Ca2+ 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 Ca2+ concentration in mouse ventricular cardiomyocytes, loss of which may contribute to cardiac dysfunction in DM1.




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