Utrophin deficiency worsens cardiac contractile dysfunction present in dystrophin-deficient mdx mice
ABSTRACT 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 (F(dev), 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 beta-adrenergic stimulation (1 micromol/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.
- SourceAvailable from: Stephan C Knipp
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- "Their specific force amplitudes at 4 Hz stimulation in wt muscle was around 30 mN/mm² which seems to be substantially larger than in our wt papillary muscles (~1 mN at 1 Hz; ~0.6 mN at 4 Hz with cross-sectional area, CSA, values between 0.3 and 0.7 mm², Methods). Therefore, our specific values would be roughly estimated to account for 1–3 mN/mm², which is a factor 10 smaller than in Janssen et al. (2005) but only five times smaller than in a more recent paper from the same group . However, under optimum conditions, paced intact heart muscle operates in the range of maximum force and, indeed, our maximum isometric force in skinned papillary muscle preparations at pCa = 4.28 accounted for ~2.2 mN which would translate to ~3–6 mN/mm² which is closer to the values given by Endoh for rabbit papillary muscle . "
ABSTRACT: OBJECTIVE: Progressive cardiomyopathy is a major cause of death in Duchenne muscular dystrophy (DMD) patients. Coupling between Ca(2+) handling and contractile properties in dystrophic hearts is poorly understood. It is also not clear whether developing cardiac failure is dominated by alterations in Ca(2+) pathways or more related to the contractile apparatus. METHODS: We simultaneously recorded force and Ca(2+) transients in field-stimulated papillary muscles from young (10 - 14 wks) wild-type (wt) and dystrophic mdx mice. RESULTS: Force amplitudes were five-fold reduced in mdx muscles despite only 30 % reduction in fura-2 ratio amplitudes. This indicated mechanisms other than systolic Ca(2+) to additionally account for force decrements in mdx muscles. pCa-force relations revealed decreased mdx myofibrillar Ca(2+) sensitivity. 'In vitro' motility assays, studied in mdx hearts here for the first time, showed significantly slower sliding velocities. mdx MLC/MHC isoforms were not grossly altered. Dystrophic hearts showed echocardiography signs of early ventricular wall hypertrophy with a significantly enlarged end-diastolic diameter 'in vivo'. However, fractional shortening was still comparable to wt mice. Changes in the contractile apparatus satisfactorily explained force drop in mdx hearts. CONCLUSIONS: We give first evidence of early hypertrophy in mdx mice and possible mechanisms for already functional impairment of cardiac muscle in DMD. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation forCellular and Molecular Medicine/Blackwell Publishing Ltd.Journal of Cellular and Molecular Medicine 09/2012; 16(12). DOI:10.1111/j.1582-4934.2012.01630.x · 3.70 Impact Factor
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- "Utrophin-deficient mice do not exhibit a detectable cardiac phenotype , and Grady et al. reported that there was no detectable histological change in utrophin-deficient cardiac muscle . However, Janssen et al.  reported that mdx/ utrn À/À dystrophin/utrophin-deficient mice exhibit contractile dysfunction to a greater degree than mdx mice, indicating that utrophin may be able to functionally compensate for dystrophin to some extent. This correlated with the up regulation and re-localization of utrophin in mdx hearts . "
ABSTRACT: Cardiac involvement in Duchenne muscular dystrophy is asymptomatic until function is severely affected. Little is known about its evolution, and few animal models are available to study potential treatments. We therefore examined cardiac function and pathology in mdx/utrn(-/-) dystrophin/utrophin-deficient mice. Decreased left ventricular fractional shortening and ejection fraction, as well as increased end-diastolic volume, left ventricle dilation, and thinning of the ventricular wall and septum develop by 15weeks. Fibrosis is also detected in the outer region of both ventricle walls and the septum and ultrastructure analysis revealed abnormalities in mitochondrial organization, size, and shape. The functional changes observed are comparable to the evolution of dilated cardiomyopathy in Duchenne muscular dystrophy, indicating that mdx/utrn(-/-) dystrophin/utrophin-deficient mice are a possible phenotypic model for cardiomyopathy in Duchenne muscular dystrophy.Neuromuscular Disorders 01/2012; 22(4):368-79. DOI:10.1016/j.nmd.2011.07.003 · 3.13 Impact Factor
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- "Pseudo-myotonia  nd nd 5m  nd none at 20-24d  nd Necrosis (histological) nd nd prominent 8w  nd nd evident at 20-24d  nd Force output (mN/mm 2 ) n d n d 1 5 a t 8 w  nd nd nd nd Heart fibrosis (% of area) nd nd nd evident at 10m in 50%  nd nd nd Abbreviations used are: Bic: biceps, Dia: diaphragm, Edl: extensor digitorum longus, Fdb: flexor digitorum brevis, Gas: gastrocnemius, Pl: plantaris, Sol: soleus, Stm: sternomastoid , TA: tibialis anterior. d: days; w: weeks; m: months; y: years; BW: body weight; CSA: cross sectional area; CK: creatine kinase; LVEDD: Left ventricular end diastolic diameter; LVESD: left ventricular end systolic diameter; nd: not determined. "
ABSTRACT: Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease that affects boys and leads to early death. In the quest for new treatments that improve the quality of life and in the search for a possible definitive cure, the use of animal models plays undoubtedly an important role. Therefore, a number of different mammalian models for DMD have been described. Much knowledge on the molecular mechanisms underlying the disease has arisen from studies in these animals. However, the use of different models does not often allow a direct comparison of results obtained in preclinical trials and therefore hinders a straightforward translational research. In the frame of "TREAT-NMD", a European Network of Excellence addressing the fragmentation in the assessment and treatment of neuromuscular diseases, we compare here the currently used mammalian animal models for DMD with the aim of selecting and recommending the most appropriate ones for preclinical efficacy testing of new therapeutic strategies.Neuromuscular Disorders 03/2009; 19(4):241-9. DOI:10.1016/j.nmd.2008.11.015 · 3.13 Impact Factor