The Role of Central Command in the Increase in Muscle Sympathetic Nerve Activity to Contracting Muscle During High Intensity Isometric Exercise

We previously demonstrated that muscle sympathetic nerve activity (MSNA) increases to contracting muscle as well as to non-contracting muscle, but this was only assessed during isometric exercise at ∼10% of maximum voluntary contraction (MVC). Given that high-intensity isometric contractions will release more metabolites, we tested the hypothesis that the metaboreflex is expressed in the contracting muscle during high-intensity but not low-intensity exercise. MSNA was recorded continuously via a tungsten microelectrode inserted percutaneously into the right common peroneal nerve in 12 participants, performing isometric dorsiflexion of the right ankle at 10, 20, 30, 40, and 50% MVC for 2 min. Contractions were immediately followed by 6 min of post-exercise ischemia (PEI); 6 min of recovery separated contractions. Cross-correlation analysis was performed between the negative-going sympathetic spikes of the raw neurogram and the ECG. MSNA increased as contraction intensity increased, reaching mean values (± SD) of 207 ± 210 spikes/min at 10% MVC (P = 0.04), 270 ± 189 spikes/min at 20% MVC (P < 0.01), 538 ± 329 spikes/min at 30% MVC (P < 0.01), 816 ± 551 spikes/min at 40% MVC (P < 0.01), and 1,097 ± 782 spikes/min at 50% MVC (P < 0.01). Mean arterial pressure also increased in an intensity-dependent manner from 76 ± 3 mmHg at rest to 90 ± 6 mmHg (P < 0.01) during contractions of 50% MVC. At all contraction intensities, blood pressure remained elevated during PEI, but MSNA returned to pre-contraction levels, indicating that the metaboreflex does not contribute to the increase in MSNA to contracting muscle even at these high contraction intensities.

Blood volume vs. deoxygenated NIRS signal: computational analysis of the effects muscle O2 delivery and blood volume on the NIRS signals

Near-infrared spectroscopy (NIRS) signals quantify the oxygenated (ΔHbMbO2) and deoxygenated (ΔHHbMb) heme group concentrations. ΔHHbMb has been preferred to ΔHbMbO2 in evaluating skeletal muscle oxygen extraction because it is assumed to be insensitive to blood volume (BV) changes, but uncertainties exist on this assumption. To analyze this assumption a computational model of oxygen transport and metabolism is used to quantify the effect of O2 delivery and BV changes on the NIRS signals from a canine model of muscle oxidative metabolism (Med.Sci.SportsExerc.,48(10)2013-2020,2016). The computational analysis accounts for microvascular (ΔHbO2, ΔHHb) and extravascular (ΔHMb, ΔHMb) oxygenated and deoxygenated forms. Simulations predicted muscle oxygen uptake and NIRS signal changes well for blood flows ranging from resting to contracting muscle. Additional NIRS signal simulations were obtained in the absence or presence of BV changes corresponding to a heme groups concentration changes (ΔHbMb=0-48μM). Under normal delivery (Q=1.0L kg-1min-1) of contracting muscle, capillary oxygen saturation (SO2) was 62% with capillary ΔHbO2 and ΔHHb of ±41μM for ΔHbMb=0. An increase of BV (ΔHbMb =24mM) caused a ΔHbO2 decrease (16mM) almost twice as much as the increase observed for ΔHHb (9μM). When SO2 increased to more than 80%, only ΔHbO2 was significantly affected by BV changes. The analysis indicates that microvascular SO2 is a key factor in determining the sensitivity of ΔHbMbO2 and ΔHHbMb to BV changes. Contrary to a common assumption, the ΔHHbMb is affected by BV changes in normal contracting muscle and even more in the presence of impaired O2 delivery.

Graded titin cleavage progressively reduces tension and uncovers the source of A-band stability in contracting muscle

The giant muscle protein titin is a major contributor to passive force; however, its role in active force generation is unresolved. Here, we use a novel titin-cleavage (TC) mouse model that allows specific and rapid cutting of elastic titin to quantify how titin-based forces define myocyte ultrastructure and mechanics. We show that under mechanical strain, as TC doubles from heterozygous to homozygous TC muscles, Z-disks become increasingly out of register while passive and active forces are reduced. Interactions of elastic titin with sarcomeric actin filaments are revealed. Strikingly, when titin-cleaved muscles contract, myosin-containing A-bands become split and adjacent myosin filaments move in opposite directions while also shedding myosins. This establishes intact titin filaments as critical force-transmission networks, buffering the forces observed by myosin filaments during contraction. To perform this function, elastic titin must change stiffness or extensible length, unveiling its fundamental role as an activation-dependent spring in contracting muscle.

Graded titin cleavage progressively reduces tension and uncovers the source of A-band stability in contracting muscle

The giant muscle protein titin is a major contributor to passive force; however, its role in active force generation is unresolved. Here, we use a novel titin-cleavage (TC) mouse model that allows specific and rapid cutting of elastic titin to quantify how titin-based forces define myocyte ultrastructure and mechanics. We show that under mechanical strain, as titin cleavage doubles from heterozygous to homozygous TC muscles, Z-disks become increasingly out of register while passive and active forces are reduced. Interactions of elastic titin with sarcomeric actin filaments are revealed. Strikingly, when titin-cleaved muscles contract, myosin-containing A-bands become split and adjacent myosin filaments move in opposite directions while also shedding myosins. This establishes intact titin filaments as critical force-transmission networks, buffering the forces observed by myosin filaments during contraction. To perform this function, elastic titin must change stiffness or extensible length, unveiling its fundamental role as an activation-dependent spring in contracting muscle.

Effects of sex and exercise training on β-adrenoreceptor mediated opposition of evoked sympathetic vasoconstriction in resting and contracting muscle of rats

This study investigated the hypothesis that β-adrenoreceptor mediated inhibition of sympathetic vasoconstriction would be enhanced in female compared to male rats, and that exercise training would augment β-adrenoreceptor inhibition of sympathetic vasoconstriction in male and female rats. Sprague-Dawley rats were randomized into sedentary (Male: n=7; Female: n=8) and exercise trained (Male: n=9; Female: n=9) groups. Following 4 weeks of exercise training or sedentary behavior, rats were anesthetized and surgically instrumented for stimulation of the lumbar sympathetic chain, muscle contraction and measurement of arterial blood pressure and femoral artery blood flow (FBF). Femoral vascular conductance (FVC) was calculated as FBF/mean arterial pressure. The percentage change of FVC in response to sympathetic stimulation delivered at 2 and 5 Hz was measured at rest and during contraction of the triceps surae muscles before and after β-adrenoreceptor blockade (Propranolol;0.075 mg·kg-1, IV). We found that, at rest, β-adrenoreceptor blockade decreased (main effect of drug, 2Hz: P <0.001; 5Hz: P<0.001) sympathetic vasoconstriction. During contraction, sympathetic vasoconstrictor responsiveness was lower (main effect of sex, 2Hz: P=0.001; 5Hz: P=0.023) in female compared to male rats, and sympatholysis was enhanced (main effect of sex, 2 Hz: P=0.001; 5Hz: P<0.001) in female rats. β-adrenoreceptor blockade decreased (main effect of drug, 2Hz: P=0.049; 5Hz: P<0.001) evoked sympathetic vasoconstriction in contracting muscle. The present study demonstrated that β-adrenoreceptors do not blunt sympathetic vasoconstriction in resting or contracting skeletal muscle of male or female rats. Sympatholysis was enhanced in female rats, however, this was not attributable to β-adrenoreceptor mediated blunting of sympathetic vasoconstriction.