Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy.

Dystrophin deficiency results in Duchenne cardiomyopathy, a primary cause of death in Duchenne muscular dystrophy (DMD). Gene therapy has shown great promise in ameliorating the cardiac phenotype in mouse models of DMD. However, it is not completely clear how much dystrophin is required to treat dystrophic heart disease. We and others have shown that mosaic dystrophin expression at the wild-type level, depending on the percentage of dystrophin positive cardiomyocytes, can either delay the onset of or fully prevent cardiomyopathy in dystrophin-null mdx mice. Many gene therapy strategies will unlikely restore dystrophin to the wild-type level in a cardiomyocyte. To determine whether low-level dystrophin expression can reduce the cardiac manifestations in DMD, we examined heart histology, ECG and hemodynamics in 21-m-old normal BL6 and two strains of BL6-background dystrophin-deficient mice. Mdx3cv mice show uniform low-level expression of a near full-length dystrophin protein in every myofiber while mdx4cv mice have no dystrophin expression. Immunostaining and western blot confirmed marginal level dystrophin expression in the heart of mdx3cv mice. Although low-level expression did not reduce myocardial histopathology, it significantly ameliorated QRS prolongation and normalized diastolic hemodynamic deficiencies. Our study demonstrates for the first time that low-level dystrophin can partially preserve heart function.

Warm acclimation alters antioxidant defences but not metabolic capacities in the Antarctic fish, Notothenia coriiceps.

The Southern Ocean surrounding the Western Antarctic Peninsula region is rapidly warming. Survival of members of the dominant suborder of Antarctic fishes, the Notothenioidei, will likely require thermal plasticity and adaptive capacity in key traits delimiting thermal tolerance. Herein, we have assessed the thermal plasticity of several cellular and biochemical pathways, many of which are known to be associated with thermal tolerance in notothenioids, including mitochondrial function, activities of aerobic and anaerobic enzymes, antioxidant defences, protein ubiquitination and degradation in cardiac, oxidative skeletal muscles and gill of Notothenia coriiceps warm acclimated to 4°C for 22 days or 5°C for 42 days. Levels of triacylglycerol (TAG) were measured in liver and oxidative and glycolytic skeletal muscles, and glycogen in liver and glycolytic muscle to assess changes in energy stores. Metabolic pathways displayed minimal thermal plasticity, yet antioxidant defences were lower in heart and oxidative skeletal muscles of warm-acclimated animals compared with animals held at ambient temperature. Despite higher metabolic rates at elevated temperature, energy storage depots of TAG and glycogen increase in liver and remain unchanged in muscle with warm acclimation. Overall, our studies reveal that N. coriiceps displays thermal plasticity in some key traits that may contribute to their survival as the Southern Ocean continues to warm.