Targeting neuroendocrine abnormalities in Parkinson’s disease with exercise

Parkinson’s Disease (PD) is a prevalent and complex age-related neurodegenerative condition for which there are no disease-modifying treatments currently available. The pathophysiological process underlying PD remains incompletely understood but increasing evidence points to multiple system dysfunction. Interestingly, the past decade has produced evidence that exercise not only reduces signs and symptoms of PD but is also potentially neuroprotective. Characterizing the mechanistic pathways that are triggered by exercise and lead to positive outcomes will improve understanding of how to counter disease progression and symptomatology. In this review, we highlight how exercise regulates the neuroendocrine system, whose primary role is to respond to stress, maintain homeostasis and improve resilience to aging. We focus on a group of hormones – cortisol, melatonin, insulin, klotho, and vitamin D – that have been shown to associate with various non-motor symptoms of PD, such as mood, cognition, and sleep/circadian rhythm disorder. These hormones may represent important biomarkers to track in clinical trials evaluating effects of exercise in PD with the aim of providing evidence that patients can exert some behavioral-induced control over their disease

Mineralocorticoid receptors modulate vascular endothelial function in human obesity

Abstract Obesity increases linearly with age and is associated with impaired vascular endothelial function and increased risk of cardiovascular disease. MRs (mineralocorticoid receptors) contribute to impaired vascular endothelial function in cardiovascular disease; however, their role in uncomplicated human obesity is unknown. Because plasma aldosterone levels are elevated in obesity and adipocytes may be a source of aldosterone, we hypothesized that MRs modulate vascular endothelial function in older adults in an adiposity-dependent manner. To test this hypothesis, we administered MR blockade (eplerenone; 100 mg/day) for 1 month in a balanced randomized double-blind placebo-controlled cross-over study to 22 older adults (ten men, 55--79 years) varying widely in adiposity [BMI (body mass index): 20--45 kg/m 2 ], but who were free from overt cardiovascular disease. We evaluated vascular endothelial function [brachial artery FMD (flow-mediated dilation)] via ultrasonography) and oxidative stress (plasma F 2 -isoprostanes and vascular endothelial cell protein expression of nitrotyrosine and NADPH oxidase p47 phox ) during placebo and MR blockade. In the whole group, oxidative stress (P > 0.05) and FMD did not change with MR blockade (6.39 + − 0.67 compared with 6.23 + − 0.73 %; P = 0.7). However, individual improvements in FMD in response to eplerenone were associated with higher total body fat (BMI: r = 0.45, P = 0.02; and dual-energy X-ray absorptiometry-derived percentage body fat: r = 0.50, P = 0.009) and abdominal fat (total: r = 0.61, P = 0.005; visceral: r = 0.67, P = 0.002; and subcutaneous: r = 0.48, P = 0.03). In addition, greater improvements in FMD with eplerenone were related to higher baseline fasting glucose (r = 0.53, P = 0.01). MRs influence vascular endothelial function in an adiposity-dependent manner in healthy older adults

Decreased maximal heart rate with aging is related to reduced β-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate

A decrease in maximal exercise heart rate (HRmax) is a key contributor to reductions in aerobic exercise capacity with aging. However, the mechanisms involved are incompletely understood. We sought to gain insight into the respective roles of intrinsic heart rate (HRint) and chronotropic β-adrenergic responsiveness in the reductions in HRmax with aging in healthy adults. HRmax (Balke treadmill protocol to exhaustion), HRint (HR during acute ganglionic blockade with intravenous trimethaphan), and chronotropic β-adrenergic responsiveness (increase in HR with incremental intravenous infusion of isoproterenol during ganglionic blockade) were determined in 15 older (65 ± 5 yr) and 15 young (25 ± 4 yr) healthy men. In the older men, HRmax was lower (162 ± 9 vs. 191 ± 11 beats/min, P < 0.0001) and was associated with a lower HRint (58 ± 7 vs. 83 ± 9 beats/min, P < 0.0001) and chronotropic β-adrenergic responsiveness (0.094 ± 0.036 vs. 0.154 ± 0.045 ΔHR/[isoproterenol]: P < 0.0001). Both HRint (r = 0.87, P < 0.0001) and chronotropic β-adrenergic responsiveness (r = 0.61, P < 0.0001) were positively related to HRmax. Accounting for the effects of HRint and chronotropic β-adrenergic responsiveness reduced the age-related difference in HRmax by 83%, rendering it statistically nonsignificant (P = 0.2). Maximal oxygen consumption was lower in the older men (34.9 ± 8.1 vs. 48.6 ± 6.7 ml·kg−1·min−1, P < 0.0001) and was positively related to HRmax (r = 0.62, P < 0.0001), HRint (r = 0.51, P = 0.002), and chronotropic β-adrenergic responsiveness (r = 0.47, P = 0.005). Our findings indicate that, together, reductions in HRint and chronotropic responsiveness to β-adrenergic stimulation largely explain decreases in HRmax with aging, with the reduction in HRint playing by far the greatest role

Protein Expression in Vascular Endothelial Cells Obtained from Human Peripheral Arteries and Veins

Studying molecular mechanisms of vascular endothelial function in humans is difficult in part because of limited access to arteries. Access to peripheral veins is more practical. We determined if differences in protein expression of endothelial cells (EC) collected from a peripheral artery are reflected in measurements made on EC obtained from peripheral veins. EC were collected from the brachial artery and an antecubital vein of 106 healthy adults (60 men and 46 women, age 18–77 years). Quantitative immunofluorescence was used to measure protein expression of endothelial nitric oxide synthase (eNOS), Ser-1177 phosphorylated eNOS, manganese superoxide dismutase, nitrotyrosine, xanthine oxidase and nuclear factor-κB p65. Protein expression in EC obtained from brachial artery and antecubital vein sampling was moderately to strongly related (r = 0.59–0.81, all p < 0.0001, mean r = 0.70). Moreover, differences between subgroups in the lowest and highest tertiles of protein expression in EC obtained from arterial samples were consistently reflected in EC obtained from venous collections. These findings indicate that interindividual and group differences in expression of several proteins involved in nitric oxide production, oxidant production, antioxidant defense and inflammatory signaling in EC obtained from brachial artery sampling are consistently reflected in EC obtained from venous samples. Thus, EC collected from peripheral veins may provide a useful surrogate for EC obtained from arteries for measurements of EC protein expression in humans

Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease

Chronic kidney disease (CKD) causes progressive skeletal myopathy involving atrophy, weakness, and fatigue. Mitochondria have been thought to contribute to skeletal myopathy; however, the molecular mechanisms underlying muscle metabolism changes in CKD are unknown. We employed a comprehensive mitochondrial phenotyping platform to elucidate the mechanisms of skeletal muscle mitochondrial impairment in mice with adenine-induced CKD. CKD mice displayed significant reductions in mitochondrial oxidative phosphorylation (OXPHOS), which was strongly correlated with glomerular filtration rate, suggesting a link between kidney function and muscle mitochondrial health. Biochemical assays uncovered that OXPHOS dysfunction was driven by reduced activity of matrix dehydrogenases. Untargeted metabolomics analyses in skeletal muscle revealed a distinct metabolite profile in CKD muscle including accumulation of uremic toxins that strongly associated with the degree of mitochondrial impairment. Additional muscle phenotyping found CKD mice experienced muscle atrophy and increased muscle protein degradation, but only male CKD mice had lower maximal contractile force. CKD mice had morphological changes indicative of destabilization in the neuromuscular junction. This study provides the first comprehensive evaluation of mitochondrial health in murine CKD muscle to our knowledge and uncovers several unknown uremic metabolites that strongly associate with the degree of mitochondrial impairment

Low muscle mass is associated with a higher risk of all–cause and cardiovascular disease–specific mortality in cancer survivors

•We conducted survival analysis for cancer survivors and their cancer-free counterparts by muscle mass.•Cancer survivors with low muscle mass are more likely to die or have fatal cardiovascular events.•Compared with their cancer-free counterparts, the effects of low muscle mass on mortality are stronger in cancer survivors. Individuals with prior cancer diagnosis are more likely to have low muscle mass (LMM) than their cancer-free counterparts. Understanding the effects of LMM on the prognosis of cancer survivors can be clinically important. The aim of this study was to investigate whether risks for all-cause and cardiovascular disease (CVD)–specific mortality differ by status of LMM in cancer survivors and a matched cohort without cancer history. We used cohort data from the 1999–2006 and 2011–2014 National Health and Nutrition Examination Survey. Participants included 946 adults surviving for ≥1 since cancer diagnosis and a matched cohort (by age, sex, and race) without cancer history (N = 1857). LMM was defined by appendicular lean mass and body height (men <7.26 kg/m2, women <5.45 kg/m2). Death was ascertained via the National Death Index and cause of death was assessed via International Classification of Diseases, Tenth Revision. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI) of LMM. The mean age of cancer survivors and matched cohort was 60.6 y (SD 15) and 60.2 y (SD 14.9), respectively. The median follow-up was 10.5 y for survivors and 10.9 y for matched cohort. Overall, 22.2% of cancer survivors and 19.7% of the matched cohort had LMM, respectively. In all, 321 survivors (33.9%) and 495 participants (26.7%) in the matched cohort died during follow-up. CVD-specific deaths were identified in 58 survivors (6.1%) and 122 participants in the matched cohort (6.6%). The multivariable Cox model suggested that LMM was positively associated with all-cause (aHR, 1.73; 95% CI, 1.31–2.29) and CVD-specific (aHR, 2.13; 95% CI, 1.14–4.00) mortality in cancer survivors. The associations between LMM and risk for all-cause (aHR, 1.24; 95% CI, 0.98–1.56) and CVD-specific (aHR, 1.21; 95% CI, 0.75–1.93) mortality were not statistically significant in the matched cohort. Cancer survivors with LMM have an increased risk for all-cause and CVD-specific mortality. This increase appears to be larger than that in counterparts without cancer history