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1Department of Physiology and Cell Biology, and 2Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio
Submitted 3 May 2005 ; accepted in final form 13 July 2005
The loss of dystrophin in patients with Duchenne muscular dystrophy (DMD) causes devastating skeletal muscle degeneration and cardiomyopathy. Dystrophin-deficient (mdx) mice have a much milder phenotype, whereas double knockout (DKO) mice lacking both dystrophin and its homolog, utrophin, exhibit the clinical signs observed in DMD patients. We have previously shown that DKO and mdx mice have similar severities of histological features of cardiomyopathy, but no contractile functional measurements of DKO heart have ever been carried out. To investigate whether DKO mice display cardiac dysfunction at the tissue level, contractile response of the myocardium was tested in small, unbranched, ultrathin, right ventricular muscles. Under near physiological conditions, peak isometric active developed tension (Fdev, in mN/mm2) at a stimulation frequency of 4 Hz was depressed in DKO mice (15.3 ± 3.7, n = 8) compared with mdx mice (24.2 ± 5.4, n = 7), which in turn were depressed compared with wild-type (WT) control mice (33.2 ± 4.5, n = 7). This reduced Fdev was also observed at frequencies within the murine physiological range; at 12 Hz, Fdev was (in mN/mm2) 11.4 ± 1.8 in DKO, 14.5 ± 4.2 in mdx, and 28.8 ± 5.4 in WT mice. The depression of Fdev was observed over the entire frequency range of 4–14 Hz and was significant between DKO versus mdx mice, as well as between DKO or mdx mice versus WT mice. Under 
-adrenergic stimulation (1 µmol/l isoproterenol), Fdev in DKO preparations was only (in mN/mm2) 14.7 ± 5.1 compared with 30.9 ± 8.9 in mdx and 41.0 ± 4.9 in WT mice. These data show that cardiac contractile dysfunction of mdx mice is generally worsened in mice also lacking utrophin.
trabeculae; papillary muscle; mouse; muscular dystrophy; -adrenergic stimulation; force frequency; heart
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