Short-term aerobic exercise prevents development of glucocorticoid myopathic features in aged skeletal muscle in a sex-dependent manner.

Older adults are vulnerable to glucocorticoid-induced muscle atrophy and weakness, with sex potentially influencing their susceptibility to those effects. Aerobic exercise can reduce glucocorticoid-induced muscle atrophy in young rodents. However, it is unknown whether aerobic exercise can prevent glucocorticoid myopathy in aged muscle. The objectives of this study were to define the extent to which sex influences the development of glucocorticoid myopathy in aged muscle, and to determine the extent to which aerobic exercise training protects against myopathy development. Twenty-four-month-old female (n = 30) and male (n = 33) mice were randomized to either sedentary or aerobic exercise groups. Within their respective groups, mice were randomized to either daily treatment with dexamethasone (DEX) or saline. Upon completing treatments, the contractile properties of the triceps surae complex were assessed in situ. DEX marginally lowered muscle mass and soluble protein content in both sexes, which was attenuated by aerobic exercise only in females. DEX increased sub-tetanic force and rate of force development only in females, which was not influenced by aerobic exercise. Muscle fatigue was higher in both sexes following DEX, but aerobic exercise prevented fatigue induction only in females. The sex-specific differences to muscle function in response to DEX treatment coincided with sex-specific changes to the content of proteins related to calcium handling, mitochondrial quality control, reactive oxygen species production, and glucocorticoid receptor in muscle. These findings define several important sexually dimorphic changes to aged skeletal muscle physiology in response to glucocorticoid treatment and define the capacity of short-term aerobic exercise to protect against those changes. KEY POINTS: There are sexually dimorphic effects of glucocorticoids on aged skeletal muscle physiology. Glucocorticoid-induced changes to aged muscle contractile properties coincide with sex-specific differences in the content of calcium handling proteins. Aerobic exercise prevents glucocorticoid-induced fatigue only in aged females and coincides with differences in the content of mitochondrial quality control proteins and glucocorticoid receptors.

Muscle fiber strain rates in the lower leg during ankle dorsi-/plantarflexion exercise.

Static quantitative magnetic resonance imaging (MRI) provides readouts of structural changes in diseased muscle, but current approaches lack the ability to fully explain the loss of contractile function. Muscle contractile function can be assessed using various techniques including phase-contrast MRI (PC-MRI), where strain rates are quantified. However, current two-dimensional implementations are limited in capturing the complex motion of contracting muscle in the context of its three-dimensional (3D) fiber architecture. The MR acquisitions (chemical shift-encoded water-fat separation scan, spin echo-echoplanar imaging with diffusion weighting, and two time-resolved 3D PC-MRI) wereperformed at 3 T. PC-MRI acquisitions and performed with and without load at 7.5% of the maximum voluntary dorsiflexion contraction force. Acquisitions (3 T, chemical shift-encoded water-fat separation scan, spin echo-echo planar imaging with diffusion weighting, and two time-resolved 3D PC-MRI) were performed with and without load at 7.5% of the maximum voluntary dorsiflexion contraction force. Strain rates and diffusion tensors were calculated and combined to obtain strain rates along and perpendicular to the muscle fibers in seven lower leg muscles during the dynamic dorsi-/plantarflexion movement cycle. To evaluate strain rates along the proximodistal muscle axis, muscles were divided into five equal segments. t-tests were used to test if cyclic strain rate patterns (amplitude > 0) were present along and perpendicular to the muscle fibers. The effects of proximal-distal location and load were evaluated using repeated measures ANOVAs. Cyclic temporal strain rate patterns along and perpendicular to the fiber were found in all muscles involved in dorsi-/plantarflexion movement (p < 0.0017). Strain rates along and perpendicular to the fiber were heterogeneously distributed over the length of most muscles (p < 0.003). Additional loading reduced strain rates of the extensor digitorum longus and gastrocnemius lateralis muscle (p < 0.001). In conclusion, the lower leg muscles involved in cyclic dorsi-/plantarflexion exercise showed cyclic fiber strain rate patterns with amplitudes that varied between muscles and between the proximodistal segments within the majority of muscles.

ß-adrenergic stimulation after rewarming does not mitigate hypothermia-induced contractile dysfunction in rat cardiomyocytes.

Victims of severe accidental hypothermia are frequently treated with catecholamines to counteract the hemodynamic instability associated with hypothermia-induced cardiac contractile dysfunction. However, we previously reported that the inotropic effects of epinephrine are diminished after hypothermia and rewarming (H/R) in an intact animal model. Thus, the goal of this study was to investigate the effects of Epi treatment on excitation-contraction coupling in isolated rat cardiomyocytes after H/R. In adult male rats, cardiomyocytes isolated from the left ventricle were electrically stimulated at 0.5 Hz and evoked cytosolic [Ca2+] and contractile responses (sarcomere length shortening) were measured. In initial experiments, the effects of varying concentrations of epinephrine on evoked cytosolic [Ca2+] and contractile responses at 37 °C were measured. In a second series of experiments, cardiomyocytes were cooled from 37 °C to 15 °C, maintained at 15 °C for 2 h, then rewarmed to 37 °C (H/R protocol). Immediately after rewarming, the effects of epinephrine treatment on evoked cytosolic [Ca2+] and contractile responses of cardiomyocytes were determined. At 37 °C, epinephrine treatment increased both cytosolic [Ca2+] and contractile responses of cardiomyocytes in a concentration-dependent manner peaking at 25-50 nM. The evoked contractile response of cardiomyocytes after H/R was reduced while the cytosolic [Ca2+] response was slightly elevated. The diminished contractile response of cardiomyocytes after H/R was not mitigated by epinephrine (25 nM) and epinephrine treatment reduced the exponential time decay constant (Tau), but did not increase the cytosolic [Ca2+] response. We conclude that epinephrine treatment does not mitigate H/R-induced contractile dysfunction in cardiomyocytes.

Immediate but not prolonged effects of submaximal eccentric vs concentric fatiguing protocols on the etiology of hamstrings' motor performance fatigue.

PURPOSE: Our study aimed to compare the immediate and prolonged effects of submaximal eccentric (ECC) and concentric (CON) fatiguing protocols on the etiology of hamstrings' motor performance fatigue. METHODS: On separate days, 16 males performed sets of 5 unilateral ECC or CON hamstrings' contractions at 80% of their 1 Repetition Maximum (1 RM) until a 20% decrement in maximal voluntary isometric contraction (MVC) torque was reached. Electrical stimulations were delivered during and after MVCs at several time points: before, throughout, immediately after (POST) and 24 h (POST 24) after the exercise. Potentiated twitch torques (T100 and T10, respectively) were recorded in response to high and low frequency paired electrical stimulations, and hamstrings' voluntary activation (VA) level was determined using the interpolated twitch technique. For statistical analysis, all indices of hamstrings' motor performance fatigue were expressed as a percentage of their respective baseline value. RESULTS: At POST, T100 (ECC: -13.3%; CON: -9.7%; p < 0.001), T10 (ECC: -5.1%; CON: -11.8%; p < 0.05) and hamstrings' VA level (ECC: -3.0%; CON: -2.4%; p < 0.001) were significantly reduced from baseline, without statistical differences between fatigue conditions. At POST24, all indices of hamstrings' motor performance fatigue returned to their baseline values. CONCLUSION: These results suggest that the contribution of muscular and neural mechanisms in hamstrings' motor performance fatigue may not depend on contraction type. This may have implications for practitioners, as ECC and CON strengthening could be similarly effective to improve hamstrings' fatigue resistance.

Specific Compounds Derived from Traditional Chinese Medicine Ameliorate Lipid-Induced Contractile Dysfunction in Cardiomyocytes.

Chronic lipid overconsumption, associated with the Western diet, causes excessive cardiac lipid accumulation, insulin resistance, and contractile dysfunction, altogether termed lipotoxic cardiomyopathy (LCM). Existing treatments for LCM are limited. Traditional Chinese Medicine (TCM) has been shown as beneficial in diabetes and its complications. The following compounds-Resveratrol, Quercetin, Berberine, Baicalein, and Isorhamnetin-derived from TCM and often used to treat type 2 diabetes. However, virtually nothing is known about their effects in the lipid-overexposed heart. Lipid-induced insulin resistance was generated in HL-1 cardiomyocytes and adult rat cardiomyocytes by 24 h exposure to high palmitate. Upon simultaneous treatment with each of the TCM compounds, we measured myocellular lipid accumulation, insulin-stimulated fatty acid and glucose uptake, phosphorylation levels of AKT and ERK1/2, plasma membrane appearance of GLUT4 and CD36, and expression of oxidative stress-/inflammation-related genes and contractility. In lipid-overloaded cardiomyocytes, all the selected TCM compounds prevented lipid accumulation. These compounds also preserved insulin-stimulated CD36 and GLUT4 translocation and insulin-stimulated glucose uptake in an Akt-independent manner. Moreover, all the TCM compounds prevented and restored lipid-induced contractile dysfunction. Finally, some (not all) of the TCM compounds inhibited oxidative stress-related SIRT3 expression, and others reduced inflammatory TNFα expression. Their ability to restore CD36 trafficking makes all these TCM compounds attractive natural supplements for LCM treatment.

Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility.

The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output and myocardial perfusion without affecting blood pressure in humans, but the cardiovascular sites of action remain obscure. Here, we test the hypothesis in rats that 3-OHB acts directly on the heart to increase cardiac contractility and directly on blood vessels to lower systemic vascular resistance. We investigate effects of 3-OHB on (a) in vivo hemodynamics using echocardiography and invasive blood pressure measurements, (b) isolated perfused hearts in Langendorff systems, and (c) isolated arteries and veins in isometric myographs. We compare Na-3-OHB to equimolar NaCl added to physiological buffers or injection solutions. At plasma concentrations of 2-4 mM in vivo, 3-OHB increases cardiac output (by 28.3±7.8%), stroke volume (by 22.4±6.0%), left ventricular ejection fraction (by 13.3±4.6%), and arterial dP/dtmax (by 31.9±11.2%) and lowers systemic vascular resistance (by 30.6±11.2%) without substantially affecting heart rate or blood pressure. Applied to isolated perfused hearts at 3-10 mM, 3-OHB increases left ventricular developed pressure by up to 26.3±7.4 mmHg and coronary perfusion by up to 20.2±9.5%. Beginning at 1-3 mM, 3-OHB relaxes isolated coronary (EC50=12.4 mM), cerebral, femoral, mesenteric, and renal arteries as well as brachial, femoral, and mesenteric veins by up to 60% of pre-contraction within the pathophysiological concentration range. Of the two enantiomers that constitute racemic 3-OHB, D-3-OHB dominates endogenously; but tested separately, the enantiomers induce similar vasorelaxation. We conclude that increased cardiac contractility and generalized systemic vasorelaxation can explain the elevated cardiac output during 3-OHB administration. These actions strengthen the therapeutic rationale for 3-OHB in heart failure management.

Endovascular aortic repair impact on myocardial contractility: A prospective study.

BACKGROUND: This study aimed to estimate if the altered sphygmic wave transmission may affect the left ventricular (LV) contractile function in patients undergoing endovascular aortic repair (EVAR). METHODS: A prospective single-centre study was carried out on consecutive patients undergoing EVAR for abdominal aortic aneurysm. A preoperative and 6-month single photon emission computed tomography (SPECT) with arterial stiffness measurement were performed to evaluate variations in pressure wave curve and myocardial perfusion parameters. RESULTS: From 2018 to 2020 a total of 16 patients were included in the study. Among the parameters evaluated, we found a measurable reduction of the reflected wave transit time from pre- to postoperative period, for both stress (115.13 ± 7.2 ms-111.1 ± 7.0 ms, p = .08) and rest SPECT acquisitions (115.3 ± 6.2 ms-112.2 ± 5.6 ms, p = .1). Unidirectional increase of both LV end-systolic volume (34 ± 9 mL-39 ± 8 mL, p = .02) and end-diastolic volume (85 ± 34 mL-89 ± 29 mL, p = .6) was also observed. Lastly, the ratio between the end-systolic pressure and the end-systolic volume (maximal systolic myocardial stiffness) decreased from 3.6 ± 1.5 mmHg/mL to 2.66 ± .74 mmHg/mL (p = .03). CONCLUSIONS: Our data showed that EVAR induced an altered transmission of the sphygmic wave associated with an early LV contractile impairment.

Exacerbated impairments in neuromuscular function when two bouts of team sport match simulations are separated by 48 h.

Intermittent team sports, involving high metabolic and mechanical demands, elicit prolonged impairments in neuromuscular function which persist for ∼48-72 h. Whether impairments in neuromuscular function are exacerbated when such exercise is repeated with incomplete recovery is unknown. This study assessed the neuromuscular, heart rate and metabolic responses to two bouts of ∼90 min modified team sport match simulations separated by 48 h in 12 competitive football players. Before and 2 min after both bouts, knee extensor isometric maximal voluntary contraction (MVC), contractile function (Qtw,pot ) and voluntary activation (VA) were measured. Heart rate (HR), sprint time, blood lactate and glucose were measured throughout both bouts. MVC was reduced relative to baseline at post-bout 1 (21 ± 12%; P = 0.003) and pre-bout 2 (14 ± 11%; P = 0.009), and was lower post-bout 2 (33 ± 14%; P < 0.001) relative to post-bout 1 (P = 0.036). Qtw,pot was reduced post-bout 1 (30 ± 11%; P < 0.001) and pre-bout 2 (9 ± 6%; P = 0.004), and was not different post-bout 2 (28 ± 8%; P < 0.001) relative to post-bout 1 (P = 0.872). VA was reduced post-bout 1 (8 ± 7%; P = 0.023), recovered pre-bout 2 (P = 0.133) and was lower post-bout 2 (16 ± 7%; P < 0.001) relative to post-bout 1 (P = 0.029). Total sprint time was longer, and HR, blood lactate and glucose were lower during bout 2 than bout 1 (P ≤ 0.021). Thus, impairments in neuromuscular function are exacerbated when high-intensity intermittent exercise is performed with incomplete recovery concurrent with accentuated reductions in VA. The lower blood lactate and glucose during the second bout might be due, at least in part, to reduced glycogen availability upon commencing exercise and consequently a greater reliance on glucose extraction. NEW FINDINGS: What is the central question of this study? There is limited evidence on whether impairments in neuromuscular function are exacerbated when prolonged high-intensity intermittent exercise is repeated with incomplete recovery: what are the neuromuscular consequences of performing two bouts of a modified team sport match simulations separated by 48 h? What is the main finding and its importance? Impairments in knee extensor force generating capacity are exacerbated concurrent with accentuated reductions in nervous system activation of muscle when prolonged high-intensity intermittent exercise is repeated with 48 h recovery.

Uterine contractile activity in healthy women throughout the menstrual cycle measured using a novel quantitative two-dimensional transvaginal ultrasound speckle tracking method.

RESEARCH QUESTION: To explore normal uterine contractile function across the menstrual cycle using a novel quantitative ultrasound method. DESIGN: This multicentre prospective observational study took place in three European centres from 2014 to 2022. Uterine contraction frequency (contractions/minute), amplitude, direction (cervix-to-fundus, C2F; fundus-to-cervix; F2C), velocity and coordination were investigated. Features were extracted from transvaginal ultrasound recordings (TVUS) using speckle tracking. Premenopausal women ≥18 years of age, with normal, natural menstrual cycles were included. A normal cycle was defined as: regular (duration 28 ± 2 days), no dysmenorrhoea, no menometrorrhagia. Four-minute TVUS were performed during the menstrual phase, mid-follicular, late follicular phase, early luteal phase and/or late luteal phase. Of the 96 recordings available from 64 women, 70 were suitable for inclusion in the analysis. RESULTS: Contraction frequency (for the posterior wall) and velocity (for the anterior uterine wall in the F2C direction) were highest in the late follicular phase and lowest in the menstrual and late luteal phases (1.61 versus 1.31 and 1.35 contractions/min, P < 0.001 and 0.81 versus 0.67 and 0.62 mm/s, P < 0.001, respectively). No significant difference was found for contraction amplitude. Contraction coordination (simultaneous contraction of the anterior and posterior walls in the same direction) was least coordinated in the mid-follicular phase (P = 0.002). CONCLUSIONS: This is the first study to objectively measure uterine contraction features in healthy women during the natural menstrual cycle on TVUS. Likewise, it introduces contraction coordination as a specific feature of uterine peristalsis. Differences in uterine contractility across the menstrual cycle are confirmed, with highest activity seen in the late follicular phase, and lowest in the late luteal phase.

Association of vastus lateralis diffusion properties with in vivo quadriceps contractile function in premenopausal women.

BACKGROUND: Diffusion tensor imaging (DTI) parameters correlate with muscle fiber composition, but it is unclear how these relate to in vivo contractile function. PURPOSE: To determine the relationship between DTI parameters of the vastus lateralis (VL) and in vivo knee extensor contractile. METHODS: Thirteen healthy, premenopausal women underwent magnetic resonance imaging of the mid-thigh to determine patellar tendon moment arm length and quadriceps cross-sectional area. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of the VL were determined using diffusion tensor imaging (DTI). Participants underwent an interpolated twitch (ITT) experiment before and after a fatiguing concentric-eccentric isokinetic knee extension (60°·s-1 ). During the ITT, supramaximal electrical stimuli were delivered to elicit twitch responses from the knee extensors before, during, and after a maximal voluntary isometric contraction (MVIC). Knee extensor-specific tension during twitch and MVIC were calculated from isometric torque data. Pearson's correlations were used to determine the relationship between muscle contractile properties and DTI parameters. RESULTS: MD and RD were moderately correlated with peak twitch force and rate of force development. FA and AD were moderately inversely related to percent change in MVIC following exercise. CONCLUSION: MD and RD are associated with in vivo quadriceps twitch properties but not voluntary strength, which may reflect the mechanical properties of constituent fiber types. FA and AD appear to relate to MVIC strength following fatiguing exercise.

Cardiac remodeling caused by cold acclimation is reversible with rewarming in zebrafish (Danio rerio).

Cold acclimation of zebrafish causes changes to the structure and composition of the heart. However, little is known of the consequences of these changes on heart function or if these changes are reversible with rewarming back to the initial temperature. In the current study, zebrafish were acclimated from 27℃ to 20°C, then after 17 weeks, a subset of fish were rewarmed to 27°C and held at that temperature for 7 weeks. The length of this trial, 23 weeks, was chosen to mimic seasonal changes in temperature. Cardiac function was measured in each group at 27°C and 20°C using high frequency ultrasound. It was found that cold acclimation caused a decrease in ventricular cross-sectional area, compact myocardial thickness, and total muscle area. There was also a decrease in end-diastolic area with cold acclimation that reversed upon rewarming to control temperatures. Rewarming caused an increase in the thickness of the compact myocardium, total muscle area, and end-diastolic area back to control levels. This is the first experiment to demonstrate that cardiac remodeling, induced by cold acclimation, is reversible upon re-acclimation to control temperature (27°C). Finally, body condition measurements reveal that fish that had been cold-acclimated and then reacclimated to 27°C, were in poorer condition than the fish that remained at 20°C as well as the control fish at week 23. This suggests that the physiological responses to the multiple changes in temperature had a significant energetic cost to the animal. SUMMARY STATEMENT: The decrease in cardiac muscle density, compact myocardium thickness and diastolic area in zebrafish caused by cold acclimation, was reversed with rewarming to control temperatures.

Berberine ameliorates the neurological dysfunction of the gastric fundus by promoting calcium channels dependent release of ACh in STZ-induced diabetic rats.

Background: It has been reported diabetic gastroparesis is related to diabetic autonomic neuropathy of the gastrointestinal tract, and berberine (BBR) could ameliorate diabetic central and peripheral neuropathy. However, the influence of BBR on the function and motility of the gastric fundus nerve is unclear. Methods: A diabetic rat model was constructed, and HE staining was used to observe the morphological changes in the gastric fundus. The changes in cholinergic and nitrogen-related neurochemical indexes and the effects of BBR on them were measured using Elisa. The effects of BBR on the neural function and motility of gastric fundus were investigated by electric field stimulation (EFS) induced neurogenic response in vitro. Results: In the early stage of STZ-induced diabetic rats, the contractile response of gastric fundus induced by EFS was disorder, disturbance of contraction amplitude, and the cell bodies of neurons in the myenteric plexus of gastric fundus presented vacuolar lesions. Administration with BBR could improve the above symptoms. BBR further enhanced the contraction response in the presence of a NOS inhibitor or the case of inhibitory neurotransmitters removal. Interestingly, the activity of ACh could affect NO release directly and the enhancement of BBR on contractile response was canceled by calcium channel blockers completely. Conclusions: In the early stage of STZ-induced diabetic rats, the neurogenic contractile response disorder of the gastric fundus is mainly related to cholinergic and nitrergic nerve dysfunction. BBR promotes the release of ACh mainly by affecting the calcium channel to improve the neurological dysfunction of the gastric fundus.

Shortening the thick filament by partial deletion of titin's C-zone alters cardiac function by reducing the operating sarcomere length range.

Titin's C-zone is an inextensible segment in titin, comprised of 11 super-repeats and located in the cMyBP-C-containing region of the thick filament. Previously we showed that deletion of titin's super-repeats C1 and C2 (TtnΔC1-2 model) results in shorter thick filaments and contractile dysfunction of the left ventricular (LV) chamber but that unexpectedly LV diastolic stiffness is normal. Here we studied the contraction-relaxation kinetics from the time-varying elastance of the LV and intact cardiomyocyte, cellular work loops of intact cardiomyocytes, Ca2+ transients, cross-bridge kinetics, and myofilament Ca2+ sensitivity. Intact cardiomyocytes of TtnΔC1-2 mice exhibit systolic dysfunction and impaired relaxation. The time-varying elastance at both LV and single-cell levels showed that activation kinetics are normal in TtnΔC1-2 mice, but that relaxation is slower. The slowed relaxation is, in part, attributable to an increased myofilament Ca2+ sensitivity and slower early Ca2+ reuptake. Cross-bridge dynamics showed that cross-bridge kinetics are normal but that the number of force-generating cross-bridges is reduced. In vivo sarcomere length (SL) measurements revealed that in TtnΔC1-2 mice the operating SL range of the LV is shifted towards shorter lengths. This normalizes the apparent cell and LV diastolic stiffness but further reduces systolic force as systole occurs further down on the ascending limb of the force-SL relation. We propose that the reduced working SLs reflect titin's role in regulating diastolic stiffness by altering the number of sarcomeres in series. Overall, our study reveals that thick filament length regulation by titin's C-zone is critical for normal cardiac function.

Contributions of alternative splicing to muscle type development and function.

Animals possess a wide variety of muscle types that support different kinds of movements. Different muscles have distinct locations, morphologies and contractile properties, raising the question of how muscle diversity is generated during development. Normal aging processes and muscle disorders differentially affect particular muscle types, thus understanding how muscles normally develop and are maintained provides insight into alterations in disease and senescence. As muscle structure and basic developmental mechanisms are highly conserved, many important insights into disease mechanisms in humans as well as into basic principles of muscle development have come from model organisms such as Drosophila, zebrafish and mouse. While transcriptional regulation has been characterized to play an important role in myogenesis, there is a growing recognition of the contributions of alternative splicing to myogenesis and the refinement of muscle function. Here we review our current understanding of muscle type specific alternative splicing, using examples of isoforms with distinct functions from both vertebrates and Drosophila. Future exploration of the vast potential of alternative splicing to fine-tune muscle development and function will likely uncover novel mechanisms of isoform-specific regulation and a more holistic understanding of muscle development, disease and aging.

Dietary nitrate increases submaximal SERCA activity and ADP transfer to mitochondria in slow-twitch muscle of female mice.

Rapid oscillations in cytosolic calcium (Ca2+) coordinate muscle contraction, relaxation, and physical movement. Intriguingly, dietary nitrate decreases ATP cost of contraction, increases force production, and increases cytosolic Ca2+, which would seemingly necessitate a greater demand for sarcoplasmic reticulum Ca2+ ATPase (SERCA) to sequester Ca2+ within the sarcoplasmic reticulum (SR) during relaxation. As SERCA is highly regulated, we aimed to determine the effect of 7-day nitrate supplementation (1 mM via drinking water) on SERCA enzymatic properties and the functional interaction between SERCA and mitochondrial oxidative phosphorylation. In soleus, we report that dietary nitrate increased force production across all stimulation frequencies tested, and throughout a 25 min fatigue protocol. Mice supplemented with nitrate also displayed an ∼25% increase in submaximal SERCA activity and SERCA efficiency (P = 0.053) in the soleus. To examine a possible link between ATP consumption and production, we established a methodology coupling SERCA and mitochondria in permeabilized muscle fibers. The premise of this experiment is that the addition of Ca2+ in the presence of ATP generates ADP from SERCA to support mitochondrial respiration. Similar to submaximal SERCA activity, mitochondrial respiration supported by SERCA-derived ADP was increased by ∼20% following nitrate in red gastrocnemius. This effect was fully attenuated by the SERCA inhibitor cyclopiazonic acid and was not attributed to differences in mitochondrial oxidative capacity, ADP sensitivity, protein content, or reactive oxygen species emission. Overall, these findings suggest that improvements in submaximal SERCA kinetics may contribute to the effects of nitrate on force production during fatigue.NEW & NOTEWORTHY We show that nitrate supplementation increased force production during fatigue and increased submaximal SERCA activity. This was also evident regarding the high-energy phosphate transfer from SERCA to mitochondria, as nitrate increased mitochondrial respiration supported by SERCA-derived ADP. Surprisingly, these observations were only apparent in muscle primarily expressing type I (soleus) but not type II fibers (EDL). These findings suggest that alterations in SERCA properties are a possible mechanism in which nitrate increases force during fatiguing contractions.

Vmeasur: A software package for experimental and clinical measurement of mesenteric lymphatic contractile function over an extended vessel length.

OBJECTIVE: Conventionally, in vivo mesenteric lymphatic contractile function is measured using a high magnification transmission microscope (field of view 0.3-1.5 mm), which precludes visualization of extended lengths of vessels embedded in mesenteric fat. Existing software is not optimized for imaging at a low magnification using a contrast agent. We aimed to develop a simple and clinically transferable method for in situ visualization, image analysis, and quantitative assessment of mesenteric lymphatic contractile function over an extended area. METHODS: Subserosal injection of various blue dyes was taken up by mesenteric lymphatics and visualized under a stereomicroscope (25×), allowing for video recording of 1.4 × 1.1 cm of intact mesentery. A new R package ("vmeasur") that combines multiple high-performance image analyses into a single workflow was developed. The edges of each vessel were determined by applying an automated threshold to each frame (with real-time manual verification). The vessel width at every point in each frame was plotted to provide contractile parameters over time and along the lymphatic vessel length. RESULTS: Contractile parameters and their differences along the length of the vessel were accurately calculated in a rodent model. In a human mesenteric lymphatic, the algorithm was also able to measure changes in diameter over length. CONCLUSION: This software offers a low cost, rapid, and accessible method to measure lymphatic contractile function over a wide area, showing differences in contractility along the length of a vessel. Because the presence of mesenteric fat has less of an impact on imaging, due to the use of an exogenous contrast agent, there is potential for clinical application.

Inorganic nitrate supplementation and blood flow restricted exercise tolerance in post-menopausal women.

Exercise tolerance appears to benefit most from dietary nitrate (NO3-) supplementation when muscle oxygen (O2) availability is low. Using a double-blind, randomized cross-over design, we tested the hypothesis that acute NO3- supplementation would improve blood flow restricted exercise duration in post-menopausal women, a population with reduced endogenous nitric oxide bioavailability. Thirteen women (57-76 yr) performed rhythmic isometric handgrip contractions (10% MVC, 30 per min) during progressive forearm blood flow restriction (upper arm cuff gradually inflated 20 mmHg each min) on three study visits, with 7-10 days between visits. Approximately one week following the first (familiarization) visit, participants consumed 140 ml of NO3- concentrated (9.7 mmol, 0.6 gm NO3-) or NO3-depleted beetroot juice (placebo) on separate days (≥7 days apart), with handgrip exercise beginning 100 min post-consumption. Handgrip force recordings were analyzed to determine if NO3- supplementation enhanced force development as blood flow restriction progressed. Nitrate supplementation increased plasma NO3- (16.2-fold) and NO2- (4.2-fold) and time to volitional fatigue (61.8 ± 56.5 s longer duration vs. placebo visit; p = 0.03). Nitrate supplementation increased the rate of force development as forearm muscle ischemia progressed (p = 0.023 between 50 and 75% of time to fatigue) with non-significant effects thereafter (p = 0.052). No effects of nitrate supplementation were observed for mean duration of contraction or relaxation rates (all p > 0.150). These results suggest that acute NO3- supplementation prolongs time-to-fatigue and speeds grip force development during progressive forearm muscle ischemia in postmenopausal women.

A soft elastomer alternative to polypropylene for pelvic organ prolapse repair: a preliminary study.

INTRODUCTION AND HYPOTHESIS: We compared the impact of a mesh manufactured from the soft elastomer polydimethylsiloxane (PDMS) to that of a widely used lightweight polypropylene (PP) mesh. To achieve a similar overall device stiffness between meshes, the PDMS mesh was made with more material and therefore was heavier and less porous. We hypothesized that the soft polymer PDMS mesh, despite having more material, would have a similar impact on the vagina as the PP mesh. METHODS: PDMS and PP meshes were implanted onto the vaginas of 20 rabbits via colpopexy. Ten rabbits served as sham. At 12 weeks, mesh-vagina complexes were explanted and assessed for contractile function, histomorphology, total collagen, and glycosaminoglycan content. Outcome measures were compared using one-way ANOVA and Kruskal-Wallis testing with appropriate post-hoc testing. RESULTS: Relative to sham, vaginal contractility was reduced following the implantation of PP (p = 0.035) but not the softer PDMS (p = 0.495). PP had an overall greater negative impact on total collagen and glycosaminoglycan content, decreasing by 53% (p < 0.001) and 54% (p < 0.001) compared to reductions of 35% (p = 0.004 and p < 0.001) with PDMS. However, there were no significant differences in the contractility, collagen fiber thickness, total collagen, and glycosaminoglycan content between the two meshes. CONCLUSIONS: Despite having a substantially higher weight, PDMS had a similar impact on the vagina compared to a low-weight PP mesh, implicating soft polymers as potential alternatives to PP. The notion that heavyweight meshes are associated with a worse host response is not applicable when comparing across materials.

Left atrial contraction strain and controlled preload alterations, a study in healthy individuals.

BACKGROUND: In order to assess left atrial contractile function in disturbed circulatory conditions, it is necessary to have a clear understanding of how it behaves in a normal resting state with changes in loading conditions. However, currently the understanding of this relationship is incomplete. We hypothesize that in healthy individuals, left atrial contraction strain and its peak strain rate are increased or decreased by increasing or decreasing preload, respectively. METHODS: Controlled maneuvers used to change preload included continuous positive airway pressure by mask (CPAP 20 cmH2O) for preload decrease, and passive leg raise (15 degrees angle) for preload increase. Cardiac ultrasound 4-chamber views of the left atria and left ventricle were acquired at baseline and during maneuver. Acquired images were post processed and analyzed offline. Comparisons were made using paired t-test and means with 95% confidence interval. RESULTS: There were 38 participants, complete results were obtained from 23 in the CPAP maneuver and 27 in the passive leg raise maneuver. For the CPAP group, left atrial contraction strain was 11.6% (10.1 to 13.1) at baseline and 12.8% (11.0 to 14.6) during the maneuver (p = 0.16). Left atrial contraction peak strain rate was - 1.7 s- 1 (- 1.8 to - 1.5) at baseline and - 1.8 s- 1 (- 2.0 to - 1.6) during the maneuver (p = 0.29). For the passive leg raise-group, left atrial contraction strain was 10.1% (9.0 to 11.2) at baseline and 10.8% (9.4 to 12.3) during the maneuver (p = 0.28). Left atrial contraction peak strain rate was - 1.5 s- 1 (- 1.6 to - 1.4) at baseline and - 1.6 s- 1 (- 1.8 to - 1.5) during the maneuver (p = 0.29). Left atrial area, an indicator of preload, increased significantly during passive leg raise and decreased during CPAP. CONCLUSION: In healthy individuals, left atrial contraction strain and its peak strain rate seem to be preload-independent. TRIAL REGISTRATION: The study was 2018-02-19 registered at clinicaltrials.gov ( NCT03436030 ).

Investigating the active contractile function of the rat paraspinal muscles reveals unique cross-bridge kinetics in the multifidus.

PURPOSE: Various aspects of paraspinal muscle anatomy, biology, and histology have been studied; however, information on paraspinal muscle contractile function is almost nonexistent, thus hindering functional interpretation of these muscles in healthy individuals and those with low back disorders. The aim of this study was to measure and compare the contractile function and force-sarcomere length properties of muscle fibers from the multifidus (MULT) and erector spinae (ES) as well as a commonly studied lower limb muscle (Extensor digitorum longus (EDL)) in the rat. METHODS: Single muscle fibers (n = 77 total from 6 animals) were isolated from each of the muscles and tested to determine their active contractile function; all fibers used in the analyses were type IIB. RESULTS: There were no significant differences between muscles for specific force (sFo) (p = 0.11), active modulus (p = 0.63), average optimal sarcomere length (p = 0.27) or unloaded shortening velocity (Vo) (p = 0.69). However, there was a significant difference in the rate of force redevelopment (ktr) between muscles (p = < 0.0001), with MULT being significantly faster than both the EDL (p = < 0.0001) and ES (p = 0.0001) and no difference between the EDL and ES (p = 0.41). CONCLUSIONS: This finding suggests that multifidus has faster cross-bridge turnover kinetics when compared to other muscles (ES and EDL) when matched for fiber type. Whether the faster cross-bridge kinetics translate to a functionally significant difference in whole muscle performance needs to be studied further.