CKD and Muscle Mitochondrial Energetics.
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ABSTRACT:
SUBMITTER: Roshanravan B
PROVIDER: S-EPMC5063821 | biostudies-literature | 2016 Oct
REPOSITORIES: biostudies-literature
Publications
CKD and Muscle Mitochondrial Energetics.
Roshanravan Baback B Kestenbaum Bryan B Gamboa Jorge J Jubrias Sharon A SA Ayers Ernest E Curtin Laura L Himmelfarb Jonathan J de Boer Ian H IH Conley Kevin E KE
American journal of kidney diseases : the official journal of the National Kidney Foundation 20160614 4
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Project description: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.
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Project description:BackgroundMuscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults.MethodsWe associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D3-creatine dilution), muscle fat infiltration (magnetic resonance imaging), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO2 peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate-to-vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: women-≥88 cm, men-≥102 cm) and gender.ResultsAmong older adults aged 75 (interquartile range: 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall (N = 362) but were positively associated among participants with a high waist circumference (β: 25.2; 95% confidence intervals [95% CI]: 11.7, 40.4; p = .0002; N = 160). Muscle fat infiltration and liver fat were positively associated (β: 15.2; 95% CI: 6.8, 24.3; p = .0003; N = 378). Carbohydrate-supported maximum oxidative phosphorylation (before adjustment) and VO2 peak (after adjustment; β: -12.9; 95% CI: -20.3, -4.8; p = .003; N = 361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (β: -4.0; 95% CI: -11.6, 4.2; p = .32; N = 321).ConclusionsSkeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted.
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Project description:Periods of elevated reactive oxygen species (ROS) production are a normal part of mitochondrial physiology. However, little is known about age-related changes in the mitochondrial response to elevated ROS in vivo. Significantly, ROS-induced uncoupling of oxidative phosphorylation has received attention as a negative feedback mechanism to reduce mitochondrial superoxide production. Here we use a novel in vivo spectroscopy system to test the hypothesis that ROS-induced uncoupling is diminished in aged mitochondria. This system simultaneously acquires (31)P magnetic resonance and near-infrared optical spectra to non-invasively measure phosphometabolite and O(2) concentrations in mouse skeletal muscle. Using low dose paraquat to elevate intracellular ROS we assess in vivo mitochondrial function in young, middle aged, and old mice. Oxidative phosphorylation was uncoupled to the same degree in response to ROS at each age, but this uncoupling was associated with loss of phosphorylation capacity and total ATP in old mice only. Using mice lacking UCP3 we demonstrate that this in vivo uncoupling is independent of this putative uncoupler of skeletal muscle mitochondria. These data indicate that ROS-induced uncoupling persists throughout life, but that oxidative stress leads to mitochondrial deficits and loss of ATP in aged organisms that may contribute to impaired function and degeneration.
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Project description:ObjectiveOur objective was to investigate the overall and sex-specific relationships between the presence and severity of knee osteoarthritis (KOA) and muscle composition, power, and energetics in older adults.MethodsMale and female patients (n = 655, mean ± SD age 76.1 ± 4.9 years; 57% female) enrolled in the Study of Muscle, Mobility, and Aging completed standing knee radiographs and knee pain assessments. Participants were divided into three groups using Kellgren-Lawrence grade (KLG) of KOA severity (0-1, 2, or 3-4). Outcome measures included whole-body muscle mass, thigh fat-free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics.ResultsOverall, the presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (P trend < 0.036). Sex-specific analysis revealed reduced energetics only in female patients with KOA (P trend < 0.007) compared to female patients without KOA. In models adjusted for age, sex, race, nonsteroidal anti-inflammatory drug administration, site or technician, physical activity, height, and participants with abdominal adiposity with KLG 3 to 4 had greater MFI (mean 0.008%, 95% confidence interval [CI] 0.004%-0.011%) and lower leg power (mean -51.56 W, 95% CI -74.03 to -29.10 W) and specific power (mean -5.38 W/L, 95% CI -7.31 to -3.45 W/L) than those with KLG 0 to 1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power, and specific power.ConclusionMuscle health is associated with the presence and severity of KOA and differs by sex. Although muscle composition and power are lower in both male and female patients with KOA, regardless of pain status, mitochondrial energetics is reduced only in female patients.
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Project description:BackgroundLower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults.MethodsThirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO2 peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATPmax) of vastus lateralis was determined in vivo by (31)P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O2 consumption) was characterized using ATPmax per St3 respiration (ATPmax/St3).ResultsIn vitro St3 respiration was significantly correlated with in vivo ATPmax (r (2) = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO2 peak (r (2) = .33, p = .006). ATPmax (r (2) = .158, p = .03) and VO2 peak (r (2) = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATPmax/St3 and VO2 peak in a multiple linear regression model improved the prediction of preferred walking speed (r (2) = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed.ConclusionsLower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.
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Project description:BackgroundMitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness, is largely understudied.MethodsIn the Study of Muscle, Mobility, and Aging, we collected vastus lateralis biopsies from older adults (n = 879, 70-94 years, 59.2% women). Maximal State 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta coefficients expressed per 1-SD increment in the independent variable.ResultsMax OXPHOS was associated with leg power for both women (β = 0.12 Watts/kg, p < .001) and men (β = 0.11 Watts/kg, p < .050). ATPmax was associated with leg power for men (β = 0.09 Watts/kg, p < .05) but was not significant for women (β = 0.03 Watts/kg, p = .11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, β women = 1.03 mL/kg/min, β men = 1.32 mL/kg/min; ATPmax β women = 0.87 mL/kg/min, β men = 1.50 mL/kg/min; all p < .001).ConclusionsHigher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power.
| S-EPMC10395564 | biostudies-literature
Project description:The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-? co-activator 1? (PGC1?), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.
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Project description:BackgroundMuscle mitochondrial dysfunction is associated with poor mobility in aging. Whether mitochondrial dysfunction predicts subsequent mobility decline is unknown.MethodsWe examined 380 cognitively normal participants aged 60 and older (53%women, 22%Black) who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr ). Mobility was measured by four walking tests. Associations of baseline kPCr with mobility changes were examined using linear mixed-effects models, adjusted for covariates. In a subset, we examined whether changes in muscle strength and mass affected these associations by adjusting for longitudinal muscle strength, lean mass, and fat mass.ResultsLower baseline kPCr was associated with greater decline in all four mobility measures (β, p-value: (0.036, 0.020) 6-m usual gait speed; (0.029, 0.038) 2.5-min usual gait speed; (0.034, 0.011) 6-m rapid gait speed; (-0.042, <0.001) 400-m time). In the subset, further adjustment for longitudinal muscle strength, lean mass, and fat mass attenuated longitudinal associations with changes in mobility (Δβ reduced 26-63%).ConclusionAmong initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. These findings need to be verified in studies correlating longitudinal changes in mitochondrial function, muscle, and mobility performance.
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