Emergent Dilated Cardiomyopathy Caused by Targeted Repair of Dystrophic Skeletal Muscle

Abstract

Duchenne muscular dystrophy (DMD) is a fatal disease characterized by deterioration of striated muscle, affecting skeletal and cardiac muscles. Recently, several therapeutic approaches have shown promise for repairing dystrophic skeletal muscles. However, these methods often leave the dystrophic heart untreated. Here we show that, in comparison to fully dystrophin-deficient animals, targeted transgenic repair of skeletal muscle, but not cardiac muscle, in otherwise dystrophin-deficient (mdx) mice paradoxically elicited a fivefold increase in cardiac injury and dilated cardiomyopathy in these animals in vivo. Skeletal muscle repair was shown to increase the voluntary activity of the mdx mice as quantified by voluntary running on the exercise wheel. Because the dystrophin-deficient heart is highly sensitive to increased stress, we hypothesize that increased activity (enabled by the repaired skeletal muscle) provided the stimulus for heightened cardiac injury and heart remodeling. In support of this hypothesis, the primary cellular compliance defect in dystrophin-deficient cardiac myocytes was found to be unchanged by skeletal muscle repair in the mdx mice. These findings provide new information on the evolution of cardiac disease in dystrophin-deficient animals and underscore the importance of implementing global striated muscle therapies for muscular dystrophy.

Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer

“…The failure to restore dystrophin in cardiac muscle could severely reduce the clinical value of antisense therapy. Of greater concern is that restoration of dystrophin in skeletal muscles but not in cardiac muscle could exacerbate the existing heart dysfunction as a result of increased workload with the improvement of skeletal muscle function (18). Here we show that PPMO as antisense oligonucleotide chemistry can achieve almost full restoration of dystrophin in cardiac and all skeletal muscles.…”

“…Because DMD patients live longer owing to improved multidisciplinary patient care, rescuing dystrophin expression in cardiac muscle becomes more critical for their longevity and quality of life (16)(17)(18)(19)(20)(21)(22). More importantly, restoration of dystrophin only in skeletal muscles may exacerbate the failure of heart function if dystrophin expression cannot be effectively restored in cardiac muscle (18). It is not understood why AON does not induce dystrophin expression effectively in cardiac muscle, but low delivery efficiency seems to be the most important contributing factor (15).…”

Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains

“…Measurements of real-time in vivo cardiovascular hemodynamics were obtained using conductance micromanometry as previously described (34,35,53,54). Mice were anesthetized and ventilated via a tracheal cannulation and ventilated via a pressure controlled ventilator with 2% isoflurane at a peak inspiratory pressure of 15 cm H2O and a respiratory rate of 60 breaths/min.…”

DOT1L regulates dystrophin expression and is critical for cardiac function

“…The increased exercise in CKO mice compared with mdx mice causes additional workload and stress on the heart, which would escalate the severity of DCM. Indeed, it has been reported that targeted repair in mdx mice using a skeletal muscle-restricted minidystrophin transgene significantly enhanced cardiac injury and DCM (Townsend et al 2008).…”