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.

Adults is not known. Purpose The purpose of this randomized controlled trial was to compare the effect of all-extremity high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on aortic pulse wave velocity (PWV) and carotid artery compliance in older adults. Methods Forty-nine sedentary older adults (age = 64 ± 1 yr), free of overt major clinical disease, were randomized to HIIT (n = 17), MICT (n = 18), or nonexercise controls (CONT; n = 14). HIIT (4 × 4 min at 90% HRpeak interspersed with 3 × 3 min active recovery at 70% HRpeak) and isocaloric MICT (70% HRpeak) were performed on an all-extremity non–weight-bearing ergometer, 4 d·wk−1 for 8 wk under supervision. Aortic (carotid to femoral PWV [cfPWV]) and common carotid artery compliance were assessed at pre- and postintervention. Results cfPWV improved by 0.5 m·s−1 in MICT (P = 0.04) but did not significantly change in HIIT and CONT (P > 0.05). Carotid artery compliance improved by 0.03 mm2·mm Hg−1 in MICT (P = 0.001), but it remained unchanged in HIIT and CONT (P > 0.05). Improvements in arterial stiffness in response to MICT were not confounded by changes in aortic or brachial blood pressure, HR, body weight, total and abdominal adiposity, blood lipids, or aerobic fitness. Conclusion All-extremity MICT, but not HIIT, improved central arterial stiffness in previously sedentary older adults free of major clinical disease. Our findings have important implications for aerobic exercise prescription in older adults....

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/m²], 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 F₂-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.