Muscle Hypertrophy Induced by Myostatin Inhibition Accelerates Degeneration in Dysferlinopathy

Because myostatin normally limits skeletal muscle growth, there is an extensive effort to develop myostatin inhibitors for clinical use. One potential concern is that in patients with muscle degenerative diseases, inducing hypertrophy may increase stress on dystrophic fibers. Here, we show that blocking the myostatin pathway in dysferlin mutant mice results in early improvement in histopathology but ultimately accelerates muscle degeneration. Hence, benefits of this approach should be weighed against these potential detrimental effects. Affymetrix Mouse Exon 1.0 ST arrays were hybridized in three biologically independent experiments with RNA from quadriceps muscles of wt, Dysf-/-, F66, F66;Dysf-/- mice, and ACVR2B/Fc-injected wt and Dysf-/- mice at the age of 10 weeks (3 duplicates in 6 different groups, 18 samples).由于肌抑素（myostatin）通常可抑制骨骼肌生长，学界正广泛开展肌抑素抑制剂的临床开发工作。但该疗法存在一项潜在隐患：对于肌肉退行性疾病患者，使用该抑制剂诱导肌纤维肥大可能会加重营养不良性肌纤维所承受的应激负荷。本研究证实，在dysferlin突变小鼠中阻断肌抑素通路，可在早期改善其组织病理学特征，但最终会加速肌肉退行性病变进程。因此，采用该疗法的收益应当与这些潜在的不良效应进行权衡考量。本研究采用Affymetrix小鼠外显子1.0 ST基因芯片（Affymetrix Mouse Exon 1.0 ST arrays），针对10周龄野生型（wild type，缩写wt）、Dysf-/-、F66、F66;Dysf-/-小鼠，以及经ACVR2B/Fc处理的野生型和Dysf-/-小鼠的股四头肌RNA开展杂交检测，共完成3次独立生物学重复实验，设置6个不同组别，每组3个重复样本，总计18个样本。