Micro-dystrophin (μDys) gene therapeutics can improve striated muscle structure and function in different animal models of Duchenne muscular dystrophy. Most studies, however, used young mdx mice that lack a pronounced dystrophic phenotype, short treatment periods, and limited muscle function tests. We, therefore, determined the relative efficacy of two previously described μDys gene therapeutics (rAAV6:μDysH3 and rAAV6:μDys5) in 6-month-old mdx mice using a 6-month treatment regimen and forced exercise. Forelimb and hindlimb grip strength, metabolic rate (VO2 max), running efficiency (energy expenditure), and serum creatine kinase levels similarly improved in mdx mice treated with either vector. Both vectors produced nearly identical dose-responses in all assays. They also partially prevented the degenerative effects of repeated high-intensity exercise on muscle histology, although none of the metrics examined was restored to normal wild-type levels. Moreover, neither vector had any consistent effect on respiration while exercising. These data together suggest that, although μDys gene therapy can improve isolated and systemic muscle function, it may be only partially effective when dystrophinopathies are advanced or when muscle structure is significantly challenged, as with high-intensity exercise. This further suggests that restoring muscle function to near-normal levels will likely require ancillary or combinatorial treatments capable of enhancing muscle strength.

中文翻译：

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微肌营养不良蛋白基因疗法部分增强老年 mdx 小鼠的运动能力。


微肌营养不良蛋白 (μDys) 基因疗法可以改善不同杜氏肌营养不良动物模型中的横纹肌结构和功能。然而，大多数研究使用的是年轻的 mdx 小鼠，这些小鼠缺乏明显的营养不良表型、治疗周期短和肌肉功能测试有限。因此，我们使用 6 个月的治疗方案和强迫运动，确定了先前描述的两种 μDys 基因疗法（rAAV6:μDysH3 和 rAAV6:μDys5）在 6 个月大的 mdx 小鼠中的相对功效。使用任一载体治疗的 mdx 小鼠的前肢和后肢握力、代谢率（最大摄氧量）、跑步效率（能量消耗）和血清肌酸激酶水平也有类似改善。两种载体在所有测定中产生几乎相同的剂量反应。它们还部分阻止了重复高强度运动对肌肉组织学的退化影响，尽管所检查的指标都没有恢复到正常野生型水平。此外，这两种载体对运动时的呼吸没有任何一致的影响。这些数据共同表明，尽管μDys基因疗法可以改善孤立性和全身性肌肉功能，但当肌营养不良症进展或肌肉结构受到显着挑战（如高强度运动）时，它可能仅部分有效。这进一步表明，将肌肉功能恢复到接近正常水平可能需要能够增强肌肉力量的辅助或组合治疗。