摘要：Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 ( Mbnl1ΔE2/ΔE2 ) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2–4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female Mbnl1ΔE2/ΔE2 mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents, Scn5a , Junctin , Junctate , Atp2a1 , Atp11a , Cacna1s , Ryr2 , intra and inter cellular transport, Clta , Stx2 , Tjp1 , cell survival, Capn3 , Sirt2 , Csda , sarcomere and cytoskeleton organization and function, Trim55 , Mapt , Pdlim3 , Pdlim5 , Sorbs1 , Sorbs2 , Fhod1 , Spag9 and structural components of the sarcomere, Myom1 , Tnnt2 , Zasp . Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease.
