Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental therapeutic approach for LGMD2B is to protect damage or improve repair of myofiber sarcolemma. Here, we compared the effects of prednisolone and vamorolone (a dissociative steroid; VBP15) on dysferlin-deficient myofiber repair. Vamorolone, but not prednisolone, stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) myofibers injured by focal sarcolemmal damage, eccentric contraction-induced injury or injury due to spontaneous in vivo activity. Vamorolone decreased sarcolemmal lipid mobility, increased muscle strength, and decreased late-stage myofiber loss due to adipogenic infiltration. In contrast, the conventional glucocorticoid prednisolone failed to stabilize dysferlin deficient muscle cell membrane or improve repair of dysferlinopathic patient myoblasts and mouse myofibers. Instead, prednisolone treatment increased muscle weakness and myofiber atrophy in B6A/J mice—findings that correlate with reports of prednisolone worsening symptoms of LGMD2B patients. Our findings showing improved cellular and pre-clinical efficacy of vamorolone compared to prednisolone and better safety profile of vamorolone indicates the suitability of vamorolone for clinical trials in LGMD2B.

DYSF基因的突变导致降低的dysferlin蛋白水平降低，从而导致患肢带状肌营养不良症的类型为2B（LGMD2B）。dysferlin促进健康肌纤维的肌膜膜修复，因此其缺陷会损害肌纤维修复并导致慢性肌肉发炎。LGMD2B的实验性治疗方法是保护损伤或改善肌纤维肉瘤的修复。在这里，我们比较了泼尼松龙和沃莫洛酮（一种解离性类固醇； VBP15）对dysferlin缺陷型肌纤维修复的影响。Vamorolone（而非泼尼松龙）稳定了dysferlin缺陷型肌细胞膜，并改善了dysferlin缺陷型小鼠（B6A / J）肌纤维的修复，这些小鼠纤维受到局灶性肌膜损伤，离心收缩诱导的损伤或体内自发性损伤的伤害活动。Vamorolone降低了肌膜脂质的流动性，增加了肌肉的力量，并减少了由于成脂作用引起的晚期肌纤维的损失。相反，常规的糖皮质激素泼尼松龙不能稳定dysferlin缺陷的肌细胞膜或改善dysferlinopathic患者成肌细胞和小鼠肌纤维的修复。相反，泼尼松龙的治疗增加了B6A / J小鼠的肌肉无力和肌纤维萎缩，这一发现与泼尼松龙使LGMD2B患者的症状恶化有关。我们的发现表明，与强的松龙相比，沃莫洛酮具有更高的细胞和临床前功效，并且沃莫洛酮具有更好的安全性，这表明沃莫洛酮是否适合在LGMD2B中进行临床试验。