Individual transcriptomic response to strength-training for myotonic dystrophy type 1 patients. Individual transcriptomic response to strength-training for myotonic dystrophy type 1 patients

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by a CTG expansion resulting in significant transcriptomic dysregulation that leads to muscle weakness and wasting. While strength training is clinically beneficial in DM1, molecular effects had not been studied. To determine whether training rescued transcriptomic defects, RNA-sequencing was performed on vastus lateralis samples from nine male DM1 patients before and after a 12-week strength training program and six male controls who did not undergo training. Differential gene expression and alternative splicing analysis were correlated with the one-repetition maximum strength evaluation method (leg extension, leg press, hip abduction, and squat). While training program-induced improvements in splicing were similar among most individuals, rescued splicing events varied considerably between individuals. Gene expression improvements were highly varied between individuals with the percentage of differentially expressed genes rescued after training strongly correlated with strength improvements. Evaluating transcriptome changes individually revealed responses to the training not evident from grouped analysis, likely due to disease heterogeneity and individual exercise response differences. Our analyses indicate that transcriptomic changes are associated with clinical outcomes in DM1 patients undergoing training and these changes are often specific to the individual and should be analyzed accordingly. Overall design: 9 male DM1 patients had quadriceps muscle biopsies taken before and after a 12-week strength training program, as well as 6 unaffected controls who did not undergo the exercise program. RNA was extracted from these biopsies and RNA-Seq was performed.

1型强直性肌营养不良（Myotonic dystrophy type 1, DM1）是成人起病型肌营养不良中最为常见的类型，其致病机制为CTG三核苷酸重复扩增，该扩增会引发显著的转录组失调，最终导致肌肉无力与肌萎缩。尽管力量训练在DM1的临床干预中已被证实具有获益效果，但此前尚未有研究探讨其分子层面的作用效应。为明确力量训练能否逆转DM1患者的转录组缺陷，研究人员对9名男性DM1患者在完成12周力量训练项目前后的股外侧肌样本，以及6名未接受任何训练的男性健康对照样本，开展了RNA测序（RNA-sequencing）实验。研究人员将差异基因表达（differential gene expression）与可变剪接分析（alternative splicing analysis）的结果，与一次重复最大负荷（one-repetition maximum）强度评估方法（包括腿部伸展、腿部推举、髋外展与深蹲四项测试）进行了关联分析。尽管多数受试者的训练诱导的剪接改善效果较为相似，但被逆转的剪接事件在个体间存在显著差异。基因表达的改善情况在个体间同样存在高度异质性，训练后被逆转的差异基因占比与受试者的力量提升程度呈显著正相关。对单个受试者的转录组变化进行单独评估后发现，分组分析无法揭示个体对训练的真实响应，这一现象可能源于疾病异质性与个体间运动响应的差异。本研究的分析结果表明，DM1患者接受力量训练后的转录组变化与临床结局密切相关，且此类变化往往具有个体特异性，因此相关分析应采用个体化的分析策略。总体实验设计：9名男性DM1患者分别在12周力量训练项目前后接受股四头肌活检，同时纳入6名未参与该运动项目的健康对照人群。研究人员从上述活检样本中提取总RNA，并进行RNA测序（RNA-Seq）实验。