TRPV1 channels in human skeletal muscle feed arteries: implications for vascular function

New Findings What is the central question of this study? We sought to determine whether human skeletal muscle feed arteries (SFMAs) express TRPV1 channels and what role they play in modulating vascular function. What is the main finding and its importance? Human SMFAs do express functional TRPV1 channels that modulate vascular function, specifically opposing α-adrenergic receptor-mediated vasocontraction and potentiating vasorelaxation, in an endothelium-dependent manner, as evidenced by the α1-receptor-mediated responses. Thus, the vasodilatory role of TRPV1 channels, and their ligand capsaicin, could be a potential therapeutic target for improving vascular function. Additionally, given the ‘sympatholytic’ effect of TRPV1 activation and known endogenous activators (anandamide, reactive oxygen species, H+, etc.), TRPV1 channels might contribute to functional sympatholysis during exercise. To examine the role of the transient receptor potential vanilloid type 1 (TRPV1) ion channel in the vascular function of human skeletal muscle feed arteries (SMFAs) and whether activation of this heat-sensitive receptor could be involved in modulating vascular function, SMFAs from 16 humans (63 ± 5 years old, range 41–89 years) were studied using wire myography with capsaicin (TRPV1 agonist) and without (control). Specifically, phenylephrine (α1-adrenergic receptor agonist), dexmedetomidine (α2-adrenergic receptor agonist), ACh and sodium nitroprusside concentration–response curves were established to assess the role of TRPV1 channels in α-receptor-mediated vasocontraction as well as endothelium-dependent and -independent vasorelaxation, respectively. Compared with control conditions, capsaicin significantly attenuated maximal vasocontraction in response to phenylephrine [control, 52 ± 8% length–tensionmax (LTmax) and capsaicin, 21 ± 5%LTmax] and dexmedetomidine (control, 29 ± 12%LTmax and capsaicin, 2 ± 3%LTmax), while robustly enhancing maximal vasorelaxation with ACh (control, 78 ± 8% vasorelaxation and capsaicin, 108 ± 13% vasorelaxation) and less clearly enhancing the sodium nitroprusside response. Denudation of the endothelium greatly attenuated the maximal ACh-induced vasorelaxation equally in the control and capsaicin conditions (∼17% vasorelaxation) and abolished the attenuating effect of capsaicin on the maximal phenylephrine response (denuded + capsaicin, 61 ± 20%LTmax). Immunohistochemistry identified a relatively high density of TRPV1 channels in the endothelium compared with the smooth muscle of the SMFAs, but because of the far greater volume of smooth muscle, total TRPV1 protein content was not significantly attenuated by denudation. Thus, SMFAs ubiquitously express functional TRPV1 channels, which alter vascular function, in terms of α1-receptors, in a predominantly endothelium-dependent manner, conceivably contributing to the functional sympatholysis and unveiling a therapeutic target

Altered skeletal muscle mitochondrial phenotype in COPD: disease vs. disuse

Patients with chronic obstructive pulmonary disease (COPD) exhibit an altered skeletal muscle mitochondrial phenotype, which often includes reduced mitochondrial density, altered respiratory function, and elevated oxidative stress. As this phenotype may be explained by the sedentary lifestyle that commonly accompanies this disease, the aim of this study was to determine whether such alterations are still evident when patients with COPD are compared to control subjects matched for objectively measured physical activity (PA; accelerometry). Indexes of mitochondrial density [citrate synthase (CS) activity], respiratory function (respirometry in permeabilized fibers), and muscle oxidative stress [4-hydroxynonenal (4-HNE) content] were assessed in muscle fibers biopsied from the vastus lateralis of nine patients with COPD and nine PA-matched control subjects (CON). Despite performing similar levels of PA (CON: 18 ± 3, COPD: 20 ± 7 daily minutes moderate-to-vigorous PA; CON: 4,596 ± 683, COPD: 4,219 ± 763 steps per day, P \u3e 0.70), patients with COPD still exhibited several alterations in their mitochondrial phenotype, including attenuated skeletal muscle mitochondrial density (CS activity; CON 70.6 ± 3.8, COPD 52.7 ± 6.5 U/mg, P \u3c 0.05), altered mitochondrial respiration [e.g., ratio of complex I-driven state 3 to complex II-driven state 3 (CI/CII); CON: 1.20 ± 0.11, COPD: 0.90 ± 0.05, P \u3c 0.05), and oxidative stress (4-HNE; CON: 1.35 ± 0.19, COPD: 2.26 ± 0.25 relative to β-actin, P \u3c 0.05). Furthermore, CS activity (r = 0.55), CI/CII (r = 0.60), and 4-HNE (r = 0.49) were all correlated with pulmonary function, assessed as forced expiratory volume in 1 s (P \u3c 0.05), but not PA (P \u3e 0.05). In conclusion, the altered mitochondrial phenotype in COPD is present even in the absence of differing levels of PA and appears to be related to the disease itself

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: −67% vs. −82%, Pi: 353% vs. 534%, pH: −0.22 vs. −0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (−3% and −36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (−15% and −33%), complex II (−36% and −23%), complex I + II (−31% and −20%), and state 3CI+CII control ratio (−24% and −39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response

Effects of Different Percentages of Blood Flow Restriction on Muscle Oxygen Saturation While Walking

International Journal of Exercise Science 16(2): 411-428, 2023. The purpose of this investigation was to determine the effect of different relative pressures of blood flow restriction (BFR) on muscle oxygen saturation (SmO2) while walking at 3.0 mph (4.83 kph). Fifteen physically active healthy adults performed seven 5-minute stages of walking at 3.0 mph with a blood flow restriction cuff applied to the proximal portion of the left or right leg while bilateral SmO2 changes were measured using near infra-red spectroscopy (NIRS) on the medial head of the gastrocnemius (GM) and vastus lateralis (VL) muscles. Other measurements including heart rate (HR), blood pressure (BP), rating of perceived exertion (RPE), and ground contact time balance (GCTB) were also collected. SmO2 measurements were analyzed using two-way repeated measures (RM) ANOVA while other measurements were analyzed using one-way RM ANOVA. We observed a significant main effect of LOP% (limb occlusion pressure) on the difference in total area of desaturation that occurred during each occlusion stage (ADS), p \u3c 0.0001 η2 = .336, early ΔSmO2, p \u3c 0.0001 in both the GAS η2 = .132 and VL η2 = .335. The results suggest that there are significant differences in SmO2 desaturation between 40%, 80%, and 100% LOP. Our findings suggest that incremental increases in LOP will bring about greater SmO2 desaturation during walking and may therefore induce a larger adaptive response on the muscles. However, increased LOP% may intensify perception of effort

Passive heat stress induces mitochondrial adaptations in skeletal muscle

AbstractThe mitochondria are central to skeletal muscle metabolic health. Impaired mitochondrial function is associated with various muscle pathologies, including insulin resistance and muscle atrophy. As a result, continuous efforts are made to find ways to improve mitochondrial health in the context of disuse and disease. While exercise is known to cause robust improvements in mitochondrial health, not all individuals are able to exercise. This creates a need for alternate interventions which elicit some of the same benefits as exercise. Passive heating (i.e., application of heat in the absence of muscle contractions) is one potential intervention which has been shown to increase mitochondrial enzyme content and activity, and to improve mitochondrial respiration. Associated with increases in mitochondrial content and/or function, passive heating can also improve insulin sensitivity in the context of type II diabetes and preserve muscle mass in the face of limb disuse. This area of research remains in its infancy, with many questions yet to be answered about how to maximize the benefits of passive heating and elucidate the mechanisms by which heat stress affects muscle mitochondria

Do Sex Differences Exist in Critical Power and W’?

Among world-class athletes, biological males tend to be faster and stronger than biological females, in part due to differences in body composition, such as lower body fat percentage and increased muscle mass. Critical power (CP) represents the highest intensity that elicits compensable and sustainable disturbances to homeostasis, while W’ is the amount of work and its associated metabolic disturbance that can be tolerated above CP. Together, CP and W’ strongly influence endurance performance. PURPOSE: To determine if sex-based differences in CP and W’ exist when normalizing for lean muscle mass. METHODS: We recruited 20 non-endurance trained individuals (10 female and 10 male, age= ~25.7yrs). VO2max was first determined through a graded exercise test on a cycle ergometer. The subjects then performed time to task failure tests at different percentages of their maximum work rate. CP and W’ were determined by linear regression of the relationship between time and work for the various tests to task failure. RESULTS: Leg lean mass was approximately 37% less in females than males (pAbsolute W’ was approximately 64% less in females than males (

The effect of the speed and range of motion of movement on the hyperemic response to passive leg movement

Abstract Passive leg movement (PLM)‐induced hyperemia is used to assess the function of the vascular endothelium. This study sought to determine the impact of movement speed and range of motion (ROM) on the hyperemic response to PLM and determine if the currently recommended protocol of moving the leg through a 90° ROM at 180°/sec provides a peak hyperemic response to PLM. 11 healthy adults underwent multiple bouts of PLM, in which either movement speed (60–240°/sec) or ROM (30–120° knee flexion) were varied. Femoral artery blood flow (Doppler Ultrasound) and mean arterial pressure (MAP; photoplethysmography) were measured throughout. Movement speed generally exhibited positive linear relationships with the hyperemic response to PLM, eliciting ~15–20% increase in hyperemia and conductance for each 30°/sec increase in speed (P < 0.05). However, increasing the movement speed above 180°/sec was physically difficult and seemingly impractical to implement. ROM exhibited curvilinear relationships (P<0.05) with hyperemia and conductance, which peaked at 90°, such that a 30° increase or decrease in ROM from 90° resulted in a 10–40% attenuation (P < 0.05) in the hyperemic response. Alterations in the balance of antegrade and retrograde flow appear to play a role in this attenuation. Movement speed and ROM have a profound impact on PLM‐induced hyperemia. When using PLM to assess vascular endothelial function, it is recommended to perform the test at the traditional 180°/sec with 90° ROM, which offers a near peak hyperemic response, while maintaining test feasibility