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1 Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
2 Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: janssen.10{at}osu.edu.
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, while mice lacking both dystrophin and its homolog, utrophin, (dko) 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, ultra-thin 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 to mdx mice (24.2±5.4, n=7), which in turn were depressed compared to 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 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, as well as between dko or mdx versus wt. Under 
-adrenergic stimulation (1µmol/L isoproterenol), Fdev in dko preparations was only 14.7±5.1 compared to, 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 devoid of utrophin.
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