Skeletal muscle capillary density is related to anaerobic threshold and claudication in peripheral artery disease.
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ABSTRACT:
SUBMITTER: Duscha BD
PROVIDER: S-EPMC8297535 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mitochondrial defects that affect cellular energy metabolism have long been implicated in the etiology of Huntington's disease (HD). Indeed, several studies have found defects in the mitochondrial functions of the central nervous system and peripheral tissues of HD patients. In this study, we investigated the in vivo oxidative metabolism of exercising muscle in HD patients. Ventilatory and cardiometabolic parameters and plasma lactate concentrations were monitored during incremental cardiopulmonary exercise in twenty-five HD subjects and twenty-five healthy subjects. The total exercise capacity was normal in HD subjects but notably the HD patients and presymptomatic mutation carriers had a lower anaerobic threshold than the control subjects. The low anaerobic threshold of HD patients was associated with an increase in the concentration of plasma lactate. We also analyzed in vitro muscular cell cultures and found that HD cells produce more lactate than the cells of healthy subjects. Finally, we analyzed skeletal muscle samples by electron microscopy and we observed striking mitochondrial structural abnormalities in two out of seven HD subjects. Our findings confirm mitochondrial abnormalities in HD patients' skeletal muscle and suggest that the mitochondrial dysfunction is reflected functionally in a low anaerobic threshold and an increased lactate synthesis during intense physical exercise.
| S-EPMC3081141 | biostudies-literature
Project description:Background Patients with peripheral artery disease (PAD) undergo frequent episodes of ischemia-reperfusion in lower extremity muscles that may negatively affect mitochondrial health and are associated with impaired mobility. We hypothesized that skeletal muscle from PAD patients will show high mitochondrial DNA heteroplasmy, especially in regions more susceptible to oxidative damage, such as the displacement loop, and that the degree of heteroplasmy will be correlated with the severity of ischemia and mobility impairment. Methods and Results Mitochondrial mutations and deletions and their relative abundance were identified by targeted mitochondrial DNA sequencing in biopsy specimens of gastrocnemius muscle from 33 PAD (ankle brachial index <0.9) and 9 non-PAD (ankle brachial index >0.9) subjects aged ?60 years. The probability of heteroplasmy per DNA base was significantly higher for PAD subjects than non-PAD within each region. In adjusted models, PAD was associated with higher heteroplasmy than non-PAD (P=0.003), but the association was limited to microheteroplasmy, that is heteroplasmy found in 1% to 5% of all mitochondrial genomes (P=0.004). Heteroplasmy in the displacement loop and coding regions were significantly higher for PAD than non-PAD subjects after adjustment for age, sex, race, and diabetes mellitus (P=0.037 and 0.004, respectively). Low mitochondrial damage, defined by both low mitochondrial DNA copy number and low microheteroplasmy, was associated with better walking performance. Conclusions People with PAD have higher "low frequency" heteroplasmy in gastrocnemius muscle compared with people without PAD. Among people with PAD, those who had evidence of least mitochondrial damage, had better walking performance than those with more mitochondrial damage. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02246660.
| S-EPMC7428597 | biostudies-literature
Project description:In people without lower extremity peripheral artery disease (PAD), mitochondrial DNA copy number declines with aging, and this decline is associated with declines in mitochondrial activity and functional performance. However, whether lower extremity ischemia is associated with lower mitochondrial DNA copy number and whether mitochondrial DNA copy number is associated with the degree of functional impairment in people with PAD is unknown. In people with and without PAD, age 65 years and older, we studied associations of the ankle-brachial index (ABI) with mitochondrial DNA copy number and associations of mitochondrial DNA copy number with functional impairment. Calf muscle biopsies were obtained from 34 participants with PAD (mean age: 73.5 years (SD 6.4), mean ABI: 0.67 (SD 0.15), mean 6-minute walk distance: 1191 feet (SD 223)) and 10 controls without PAD (mean age: 73.1 years (SD 4.7), mean ABI: 1.14 (SD 0.07), mean 6-minute walk distance: 1387 feet (SD 488)). Adjusting for age and sex, lower ABI values were associated with higher mitochondrial DNA copy number, measured in relative copy number (ABI<0.60: 914, ABI 0.60-0.90: 731, ABI 0.90-1.50: 593; p trend=0.016). The association of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity differed significantly between participants with versus without PAD ( p-value for interaction=0.001 and p=0.015, respectively). The correlation coefficient between mitochondrial DNA copy number and the 6-minute walk distance was 0.653 ( p=0.056) among people without PAD and -0.254 ( p=0.154) among people with PAD and ABI < 0.90. In conclusion, lower ABI values are associated with increased mitochondrial DNA copy number. Associations of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity significantly differed between people with versus without PAD, with stronger positive associations observed in people without PAD than in people with PAD. The cross-sectional and exploratory nature of the analyses precludes conclusions regarding causal inferences. ClinicalTrials.gov Identifier: NCT02246660.
| S-EPMC6100735 | biostudies-literature
Project description:Work from our laboratory documents pathological events, including myofiber oxidative damage and degeneration, myofibrosis, micro-vessel (diameter = 50-150 ?m) remodeling, and collagenous investment of terminal micro-vessels (diameter ? 15 µm) in the calf muscle of patients with Peripheral Artery Disease (PAD). In this study, we evaluate the hypothesis that the vascular pathology associated with the legs of PAD patients encompasses pathologic changes to the smallest micro-vessels in calf muscle. Biopsies were collected from the calf muscle of control subjects and patients with Fontaine Stage II and Stage IV PAD. Slide specimens were evaluated by Quantitative Multi-Spectral and Fluorescence Microscopy. Inter-myofiber collagen, stained with Masson Trichrome (MT), was increased in Stage II patients, and more substantially in Stage IV patients in association with collagenous thickening of terminal micro-vessel walls. Evaluation of the Basement Membrane (BM) of these vessels reveals increased thickness in Stage II patients, and increased thickness, diameter, and Collagen I deposition in Stage IV patients. Coverage of these micro-vessels with pericytes, key contributors to fibrosis and BM remodeling, was increased in Stage II patients, and was greatest in Stage IV patients. Vascular pathology of the legs of PAD patients extends beyond atherosclerotic main inflow arteries and affects the entire vascular tree-including the smallest micro-vessels.
| S-EPMC7464726 | biostudies-literature
Project description:The arterial blockage in patients with peripheral arterial disease (PAD) restricts oxygen delivery to skeletal muscles distal to the blockage. In advanced-stage PAD patients, this creates a chronic ischemic condition in the affected muscles. However, in the majority of PAD patients, the muscles distal to the blockage only become ischemic during physical activity when the oxygen demands of these muscles are increased. Therefore, the skeletal muscle of most PAD patients undergoes repeated cycles of low-grade ischemia-reperfusion each time the patient is active and then rests. This has been speculated to contribute to the biochemical and morphological myopathies observed in PAD patients. The current study aimed to determine, using a rodent model, whether repeated hind limb muscle contractions during blood flow restriction to the hind limb muscles increases NF-?B activity. We, subsequently, determined whether an increase in NF-?B activity during this condition is required for the increased transcription of specific atrophy-related genes and muscle fiber atrophy. We found that hind limb muscle contractions during blood flow restriction to the limb increased NF-?B activity, the transcription of specific atrophy-related genes, and caused a 35% decrease in muscle fiber cross-sectional area. We further found that inhibition of NF-?B activity, via gene transfer of a dominant-negative inhibitor of ?B? (d.n. I?B?), prevented the increase in atrophy gene expression and muscle fiber atrophy. These findings demonstrate that when blood flow to skeletal muscle is restricted, repeated cycles of muscle contraction can cause muscle fiber atrophy that requires NF-?B-I?B? signaling.
| S-EPMC6195647 | biostudies-literature
Project description:Chronic and acute ischemic diseases-peripheral artery disease, coronary artery disease, stroke-result in tissue damage unless blood flow is maintained or restored in a timely manner. Mice of different strains recover from arteriolar ligation (by increasing collateral blood flow) at different speeds. We quantify the spatio-temporal patterns of microvascular network remodeling following arteriolar ligation in different mouse strains to better understand inter-individual variability.Whole-muscle spinotrapezius microvascular networks of mouse strains C57Bl/6, Balb/c and CD1 were imaged using confocal microscopy following ligation of feeding arterioles.Baseline arteriolar structures of C57Bl/6 and Balb/c mice feature heavily ramified arcades and unconnected dendritic trees, respectively. This network angioarchitecture identifies ischemia-protected and ischemia-vulnerable tissues; unlike C57Bl/6, downstream capillary perfusion in Balb/c spinotrapezius is lost following ligation. Perfusion recovery requires arterialization (expansion and investment of mural cells) of a subset of capillaries forming a new low-resistance collateral pathway between arteriolar trees. Outbred CD1 exhibit either Balb/c-like or C57Bl/6-like spinotrapezius angioarchitecture, predictive of response to arteriolar ligation.This collateral capillary arterialization process may explain the reported longer time required for blood flow recovery in Balb/c hindlimb ischemia, as low-resistance blood flow pathways along capillary conduits must be formed ("arterialization") before reperfusion.
| S-EPMC2907254 | biostudies-literature
Project description:Peripheral arterial disease (PAD), caused by atherosclerosis, leads to limb ischemia, muscle damage, and impaired mobility in the lower extremities. Recent studies suggest that circadian rhythm disruptions can hinder vascular repair during ischemia, but the specific tissues involved and the impact on muscle health remain unclear. This study investigates the role of the skeletal muscle circadian clock in muscle adaptation to ischemic stress using a surgical mouse model of hindlimb ischemia. We used mice with specific genetic loss of the circadian clock activator, BMAL1, in adult skeletal muscle tissues (Bmal1muscle). Bmal1muscle mice and controls underwent femoral artery ligation surgery to induce hindlimb ischemia. Laser doppler imaging was used to assess limb perfusion at various time points after the surgery. Muscle tissues were analyzed with RNA sequencing and histological examination to investigate PAD-related muscle pathologies. Additionally, we studied the role of BMAL1 in muscle fiber adaptation to hypoxia using RNA and ATAC sequencing analyses in primary myotube culture model. Disrupted expression of circadian rhythm-related genes was observed in existing RNA-seq datasets from PAD patient-derived endothelial cells and ischemic limb skeletal muscles. Genetic loss of Bmal1 specifically in adult mouse skeletal muscle tissues delayed reperfusion recovery following induction of hindlimb ischemia. Histological examination of muscle tissues showed reduced regenerated myofiber number and a decreased proportion of type IIB fast-twitch myofibers in Bmal1musc mouse muscles in the ischemic limbs, but not in their contralateral non-ischemic limbs. Transcriptomic analysis revealed abrogated metabolic, angiogenic, and myogenic pathways relevant to hypoxia-adaptation in Bmal1musc mouse muscles. These changes were corroborated in Bmal1-deficient cultured primary myotubes cultured under hypoxic conditions.
2024-09-01 | GSE275811 | GEO
Project description:Claudication is a common and disabling symptom of peripheral artery disease that can be treated with medication, supervised exercise (SE), or stent revascularization (ST).We randomly assigned 111 patients with aortoiliac peripheral artery disease to receive 1 of 3 treatments: optimal medical care (OMC), OMC plus SE, or OMC plus ST. The primary end point was the change in peak walking time on a graded treadmill test at 6 months compared with baseline. Secondary end points included free-living step activity, quality of life with the Walking Impairment Questionnaire, Peripheral Artery Questionnaire, Medical Outcomes Study 12-Item Short Form, and cardiovascular risk factors. At the 6-month follow-up, change in peak walking time (the primary end point) was greatest for SE, intermediate for ST, and least with OMC (mean change versus baseline, 5.8±4.6, 3.7±4.9, and 1.2±2.6 minutes, respectively; P<0.001 for the comparison of SE versus OMC, P=0.02 for ST versus OMC, and P=0.04 for SE versus ST). Although disease-specific quality of life as assessed by the Walking Impairment Questionnaire and Peripheral Artery Questionnaire also improved with both SE and ST compared with OMC, for most scales, the extent of improvement was greater with ST than SE. Free-living step activity increased more with ST than with either SE or OMC alone (114±274 versus 73±139 versus -6±109 steps per hour), but these differences were not statistically significant.SE results in superior treadmill walking performance than ST, even for those with aortoiliac peripheral artery disease. The contrast between better walking performance for SE and better patient-reported quality of life for ST warrants further study.URL: http://clinicaltrials.gov/ct/show/NCT00132743?order=1. Unique identifier: NCT00132743.
| S-EPMC3374869 | biostudies-literature
Project description:BackgroundDecreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies.MethodsBiopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture.ResultsHistological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology.ConclusionDPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage).Clinical relevanceRestoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.
| S-EPMC8783612 | biostudies-literature
Project description:ObjectiveThe effect of insulin on blood flow distribution within muscle microvasculature has been suggested to be important for glucose metabolism. However, the "capillary recruitment" hypothesis is still controversial and relies on studies using indirect contrast-enhanced ultrasound (CEU) methods.MethodsWe studied how hyperinsulinemia effects capillary blood flow in rat extensor digitorum longus (EDL) muscle during euglycemic hyperinsulinemic clamp using intravital video microscopy (IVVM). Additionally, we modeled blood flow and microbubble distribution within the vascular tree under conditions observed during euglycemic hyperinsulinemic clamp experiments.ResultsEuglycemic hyperinsulinemia caused an increase in erythrocyte (80 ± 25%, P < .01) and plasma (53 ± 12%, P < .01) flow in rat EDL microvasculature. We found no evidence of de novo capillary recruitment within, or among, capillary networks supplied by different terminal arterioles; however, erythrocyte flow became slightly more homogenous. Our computational model predicts that a decrease in asymmetry at arteriolar bifurcations causes redistribution of microbubble flow among capillaries already perfused with erythrocytes and plasma, resulting in 25% more microbubbles flowing through capillaries.ConclusionsOur model suggests increase in CEU signal during hyperinsulinemia reflects a redistribution of arteriolar flow and not de novo capillary recruitment. IVVM experiments support this prediction showing increases in erythrocyte and plasma flow and not capillary recruitment.
| S-EPMC7064932 | biostudies-literature