Parkinson?s disease (PD) is a leading neurodegenerative disease among aging adults, affecting ~1% of the population over age 65. The well-established root cause of PD is loss of dopaminergic neurons in the substantia nigra pars compacta, part of the basal ganglia in the midbrain, leading to the classic motor symptoms (tremor, bradykinesia, rigidity, postural instability, gait problems) and a host of non-motor symptoms (e.g., depression, anxiety, sleep disorders, loss of smell, and cognitive decline). Prior to our laboratory?s recent work, it was unknown whether PD progression extended to a unique phenotype in limb skeletal muscles. We found an exaggerated pathological grouping of type I (slow, oxidative) myofibers in PD thigh muscle compared to age- matched non-PD peers. More severe type I grouping in PD was associated with exaggerated motor unit activation during weight-bearing tasks (i.e., sit-to-stand), indicating increased physiologic difficulty, along with a worsened mobility scores, suggesting that type I myofiber grouping may contribute to or progress along with the classic motor symptoms of PD. Abnormal type I grouping is indicative of heightened rates of denervation- reinnervation cycling, with denervated myofibers characterized by recapitulated expression of developmental factors [e.g., neonatal voltage-gated sodium channel 1.5 (Nav1.5) and neural cell adhesion molecule (NCAM)]. In our recent work, type I grouping in PD was accompanied by elevated Nav1.5 mRNA expression and differential mRNA and/or protein expression of key components involved in regulating neuromuscular junction (NMJ) stability. In a recent transcriptome-wide RNA-Seq investigation, we further demonstrated that the degree of type I myofiber grouping was linked to gene expression networks involved in neuromuscular communication, neural development, and cell adhesion and survival. We previously found that high-intensity resistance exercise rehabilitation training (RT) successfully reversed several pathologies of PD, including type I myofiber grouping. We suspect this change is likely mediated by molecular transducers regulating NMJ stability, such as microRNAs (miRNAs), which have recently emerged as cross-tissue mediators of gene expression. In further support, a number of muscle-expressed miRNAs associated with type I myofiber grouping in our recent work target genes associated with neuronal survival, neurite outgrowth, and axon guidance. These combined findings raise the central hypothesis that the extreme motor unit remodeling phenotype seen in PD, and its partial reversal with RT, will be linked to differentially expressed miRNA networks in conjunction with alterations in the prevalence of denervated myofibers. We will test this hypothesis with two aims.
Aim 1 : We will identify serum exosome-isolated miRNAs unique to PD and determine the impact of 16 wk RT on this miRNA expression profile using small RNA- Seq.
Aim 2 : We will quantify the magnitude and distribution of denervated myofibers from our PD replicate cohort, enabling us to determine the impact of 16 wk RT. This research is expected to markedly advance the field, while providing innovative and fruitful training and career development for the applicant.
Parkinson?s disease (PD) affects ~1% of the population over 65y, and there is currently no treatment to completely reverse the motor symptoms that eventually progress toward cognitive decline, dementia, and loss of independence in the vast majority of those with PD. However, exercise training is a potent rehabilitative therapy in individuals with PD, and preliminary data suggest that these benefits are likely reflected by improvements in the muscle molecular environment and accompanying phenotypic changes that facilitate neuromuscular junction stability. Further examination of putative contributors to exercise-induced improvements in physiological functioning in PD (e.g., post-transcriptional regulation of gene expression and skeletal muscle fiber denervation-reinnervation cycling) will enable enhanced application of exercise as an adjuvant treatment to improve motor function and overall quality of life in this population.
