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

Abstract

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-Seq was performed on vastus lateralis samples from 9 male patients with DM1 before and after a 12-week strength-training program and 6 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, and the percentage of differentially expressed genes rescued after training were 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 patients with DM1 undergoing training and that these changes are often specific to the individual and should be analyzed accordingly.

Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1

“…CDKN1A, TP63) 55 , are negatively correlated with muscle strength in DM1 51 . Notably, recent findings from DM1 patients' transcriptomic response to strength training showed that CDKN1A is one of the few genes that is correlated to clinical benefits (i.e., the individuals that experienced greater clinical benefits from strength training showed a stronger reduction in CDKN1A expression) 56 . RNAseq performed in other tissues such as the frontal cortex showed an enrichment in inflammatory genes compared to healthy individuals, suggesting that the pro-inflammatory signature is a common feature in different DM1 tissues 57 .…”