Skeletal muscle transcriptional networks linked to type I myofiber grouping in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder impacting cognition, movement, and quality of life in >10 million individuals worldwide. We recently characterized and quantified a skeletal muscle pathology in PD represented by exaggerated type I myofiber grouping presumed to result from denervation-reinnervation processes. Our previous findings indicated that impaired neuromuscular junction integrity may be involved in type I grouping, which is associated with excessive motor unit activation during weight-bearing tasks. In this study, we performed transcriptional profiling to test the hypothesis that type I grouping severity would link to distinct gene expression networks. We generated transcriptome-wide poly(A) RNA-Seq data from skeletal muscle of individuals with PD [ n = 12 (9 men, 3 women); 67 ± 2 yr], age- and sex-matched older adults ( n = 12; 68 ± 2 yr), and sex-matched young adults ( n = 12; 30 ± 1 yr). Differentially expressed genes were evaluated across cohorts. Weighted gene correlation network analysis (WGCNA) was performed to identify gene networks most correlated with indicators of abnormal type I grouping. Among coexpression networks mapping to phenotypes pathologically increased in PD muscle, one network was highly significantly correlated to type I myofiber group size and another to percentage of type I myofibers found in groups. Annotation of coexpressed networks revealed that type I grouping is associated with altered expression of genes involved in neural development, postsynaptic signaling, cell cycle regulation and cell survival, protein and energy metabolism, inflammation/immunity, and posttranscriptional regulation (microRNAs). These transcriptomic findings suggest that skeletal muscle may play an active role in signaling to promote myofiber survival, reinnervation, and remodeling, perhaps to an extreme in PD. NEW & NOTEWORTHY Despite our awareness of the impact of Parkinson’s disease (PD) on motor function for over two centuries, limited attention has focused on skeletal muscle. We previously identified type I myofiber grouping, a novel indicator of muscle dysfunction in PD, presumably a result of heightened rates of denervation/reinnervation. Using transcriptional profiling to identify networks associated with this phenotype, we provide insight into potential mechanistic roles of skeletal muscle in signaling to promote its survival in PD.

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

“…Application of the PLIER algorithm identified two gene programs that are altered by PD and rescued by RT. The present findings, in combination with our previous work (Kelly et al, 2018a;Lavin et al, 2019) strengthen our understanding of skeletal muscle as a communicative tissue in exercise, aging, and neurodegenerative disease. Further, findings support that, by optimizing muscle health throughout an exercise training regimen, therapeutic effects seen in other tissues and systems may have a mechanistic basis in alterations at the level of the skeletal muscle transcriptome.…”

“…Our laboratory has also previously shown that coordinated motor unit activation in individuals with PD markedly improves following RT, indicating reduced difficulty performing a functional sit-to-stand task (Kelly et al, 2014). This improvement is believed to be a reflection of an RT-induced reduction in average motor unit size, which has previously been shown to increase with aging (Kelly et al, 2018b;Roberts et al, 2018) and specifically PD (Caviness et al, 2002;Kelly et al, 2018a;Lavin et al, 2019). The histological manifestation of motor unit remodeling in the vastus lateralis is type I myofiber grouping, a skeletal muscle phenotype noticeable in aged adults (Stalberg and Fawcett, 1982;Piasecki et al, 2016) but further exaggerated in individuals with PD (Kelly et al, 2018a).…”

“…For an additional exploratory analysis, we included seven additional baseline PD subjects, 12 sex-matched young adults (YA), and 12 age-and sex-matched healthy older adults (OA). Together with the five exercisers, these 36 individuals were previously extensively profiled at baseline in a transcriptomewide RNA-Seq analysis of type I myofiber grouping (Lavin et al, 2019). Studies for which the individuals volunteered have been reported previously (Kosek et al, 2006;Merritt et al, 2013;Kelly et al, 2014) and detailed recruitment and eligibility information can be found therein.…”

“…We previously demonstrated that heightened expression of transcripts involved in neural development was associated with type I grouping in PD skeletal muscle (Lavin et al, 2019), believed to be a result of denervation-reinnervation processes accelerated in PD (Lexell and Downham, 1991;Kelly et al, 2018a). Presently, we detected reversal in direction of expression of a handful of these genes with RT, including transcription factors NFAT (nuclear factor of activated T-cells)5 and ZNF (zinc finger proteins) 689 and 24, the latter of which enables cell cycle progression in early neural development (Khalfallah et al, 2009).…”

“…Thus, along with modulating the severity of other symptoms, exercise-induced demands placed on skeletal muscle partially undo a hallmark pathology in peripheral tissue. We have previously investigated this phenotype extensively (Kelly et al, 2018a,b;Lavin et al, 2019) demonstrating that muscle communication with the nervous system is concordantly altered. Due to the apparently active role of muscle in signaling to promote survival, reinnervation, and remodeling, maintenance of muscle health through exercise may be of critical importance in PD or older individuals at risk for PD.…”