Parkinson's disease (PD) is the most common motor neurodegenerative disease, and neuromuscular function deficits associated with PD contribute to disability. Targeting these symptoms, our laboratory has previously evaluated 16-week high-intensity resistance exercise as rehabilitative training (RT) in individuals with PD. We reported significant improvements in muscle mass, neuromuscular function (strength, power, and motor unit activation), indices of neuromuscular junction integrity, total and motor scores on the unified Parkinson's disease rating scale (UPDRS), and total and sub-scores on the 39-item PD Quality of Life Questionnaire (PDQ-39), supporting the use of RT to reverse symptoms. Our objective was to identify transcriptional networks that may contribute to RT-induced neuromuscular remodeling in PD. We generated transcriptome-wide skeletal muscle RNA-sequencing in 5 participants with PD [4M/1F, 67 ± 2 years, Hoehn and Yahr stages 2 (n = 3) and 3 (n = 2)] before and after 16-week high intensity RT to identify transcriptional networks that may in part underpin RT-induced neuromuscular remodeling in PD. Following RT, 304 genes were significantly upregulated, notably related to remodeling and nervous system/muscle development. Additionally, 402 genes, primarily negative regulators of muscle adaptation, were downregulated. We applied the recently developed Pathway-Level Information ExtractoR (PLIER) method to reveal coordinated gene programs (as latent variables, LVs) that differed in skeletal muscle among young (YA) and old (OA) healthy adults and PD (n = 12 per cohort) at baseline and in PD pre-vs. post-RT. Notably, one LV associated with angiogenesis, axon guidance, and muscle remodeling was significantly lower in PD than YA at baseline and was significantly increased by exercise. A different LV annotated to denervation, autophagy, and apoptosis was increased in both PD and OA relative to YA and was also reduced by 16-week RT in PD. Thus, this analysis identified two novel skeletal
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.
Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome‐wide association study approach. Methods Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self‐reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m2). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non‐Hispanic White (NHW) participants with COPD. Single variant and gene‐based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein–protein interaction (PPI) data. Results At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3–5.6, P = 3.2 × 10−8) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane‐bound protein ephrin‐A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin‐responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene‐based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling. Conclusions The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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