Muscle Responses Research Articles

Reliability of a novel neck external loading dynamometer.

Cervistab is an electro-pneumatic device that produces flexion push-loading events in an ecological rugby position (i.e. similar to on-pitch position) to assess neck extensors muscle response to a flexion perturbation. This response is important for preventing head/neck injuries in Rugby, however there is a clear lack of validated devices in the literature. This study tested the reliability of this new device designed to investigate the extensor neck muscle response to flexion head push-loading event. Twelve healthy volunteers were tested with Cervistab in a test/retest protocol. Participants experienced push-loading events with preloading on extensors muscles at 50% and 20% of their maximum voluntary isometric extension strength. Muscle mechanical latency, non-reflex and reflex rates of force development were measured twice, 7days apart. Reliability was assessed by intraclass correlation coefficient (ICC), coefficient of variation (CV), and the Bland and Altman graphical approach. For both preloading conditions, muscle mechanical latency showed good ICC values from 0.81 to 0.88 and good CV (3.5%). Non-reflex and reflex rates of force development showed good reliability with ICC ranging from 0.78 to 0.89, and moderate CV values ranging from 8.5% to 14.5%, depending on the preloading condition (20% and 50% of maximal isometric extension contraction respectively). Bland and Altman plots showed no significant fixed or proportional bias. Overall, the reliability of measurements obtained with Cervistab is good. Cervistab can be used in practice to improve our understanding of the neuromechanical factors that influence neck stability, to help prevent head/neck injuries and to guide the decision to return to play after a head or neck injury.

Time-series transcriptomics reveals distinctive mRNA expression dynamics associated with gene ontology specificity and protein expression in skeletal muscle after electrical stimulation-induced resistance exercise.

Resistance exercise upregulates and downregulates the expression of a wide range of genes in skeletal muscle. However, detailed analysis of mRNA dynamics such as response rates and temporal patterns of the transcriptome after resistance exercise has not been performed. We aimed to clarify the dynamics of time-series transcriptomics after resistance exercise. We used electrical stimulation-induced muscle contraction as a resistance exercise model (5 sets × 10 times of 3 s of 100-Hz electrical stimulation) on the tibialis anterior muscle of rats and measured the transcriptome in the muscle before and at 0, 1, 3, 6, and 12 h after muscle contractions by RNA sequencing. We also examined the relationship between the parameters of mRNA dynamics and the increase in protein expression at 12 h after muscle contractions. We found that the function of the upregulated genes differed after muscle contractions depending on their response rate. Genes related to muscle differentiation and response to mechanical stimulus were enriched in the sustainedly upregulated genes. Furthermore, there was a positive correlation between the magnitude of upregulated mRNA expression and the corresponding protein expression level at 12 h after muscle contractions. Although it has been theoretically suggested, this study experimentally demonstrated that the magnitude of the mRNA response after electrical stimulation-induced resistance exercise contributes to skeletal muscle adaptation via increases in protein expression. These findings suggest that mRNA expression dynamics such as response rate, a sustained upregulated expression pattern, and the magnitude of the response contribute to mechanisms underlying adaptation to resistance exercise.

Short-Latency Trigeminocervical Reflex Obtained Without Muscle Activation: Topographic Distribution and Methodological Approach

Purpose: Electrical stimulation of trigeminal nerve branches elicits early and late reflex responses in the cervical muscles, known as the trigeminocervical reflex (TCR). This study aimed to evaluate the neurophysiological aspects, stimulation patterns, and topographic distribution of short-latency TCR components in humans in the absence of voluntary muscle activation. Methods: This prospective observational study included 30 participants. Trigeminocervical reflex responses were simultaneously recorded from the bilateral sternocleidomastoid, trapezius, and splenius capitis muscles (without voluntary muscle activation), after electrical stimulation of the supraorbital and infraorbital nerves. Two different stimulation protocols were evaluated: a 3 Hz stimulation protocol (using averaging) and a single-pulse stimulation protocol. Results: Using a 3 Hz stimulation protocol, short-latency TCR responses were recorded in the sternocleidomastoid, trapezius, and splenius capitis muscles, ipsilateral and/or contralateral, but with variable recordability depending on the recording site. The most reliable response was obtained in ipsilateral sternocleidomastoid muscle. To the best of our knowledge, this is the first study to demonstrate the elicitation of short-latency TCR components in the sternocleidomastoid muscle in the absence of voluntary muscle activation in humans without craniocervical junction disorders or lower brainstem abnormalities. Conclusions: The choice of an appropriate stimulation protocol is particularly relevant for recording short-latency TCR components, considering that the visualization of early or late responses seems to be facilitated by different stimulation methodologies.

Molecular signaling predicts corticospinal axon growth state and muscle response plasticity induced by neuromodulation

Electrical motor cortex stimulation can produce corticospinal system plasticity and enhance motor function after injury. We investigate molecular mechanisms of structural and physiological plasticity following electrical neuromodulation, focusing on identifying molecular predictors, or biomarkers, for durable plasticity. We used two neuromodulation protocols, repetitive multipulse stimulation (rMPS) and patterned intermittent theta burst stimulation (iTBS), incorporating different stimulation durations and follow-up periods. We compared neuromodulation efficacy in promoting corticospinal tract (CST) sprouting, motor cortex muscle evoked potential (MEP) LTP-like plasticity, and their associated molecular underpinnings. Only iTBS produced CST sprouting after short-term neuromodulation (1 d of stimulation; 9-d survival for sprouting expression); both iTBS and rMPS produced sprouting with long-term (10-d) neuromodulation. Significant mTOR signaling activation and phosphatase and tensin homolog (PTEN) protein deactivation predicted axon growth across all neuromodulation conditions that produced significant sprouting. Both neuromodulation protocols, regardless of duration, were effective in producing MEP enhancement. However, persistent LTP-like enhancement of MEPs at 30 d was only produced by long-term iTBS. Statistical modeling suggests that Stat3 signaling is the key mediator of MEP enhancement. Cervical spinal cord injury (SCI) alone did not affect baseline molecular signaling. Whereas iTBS and rMPS after SCI produced strong mTOR activation and PTEN deactivation, only iTBS produced Stat3 activation. Our findings support differential molecular biomarkers for neuromodulation-dependent structural and physiological plasticity and show that motor cortex epidural neuromodulation produces molecular changes in neurons that support axonal growth after SCI. iTBS may be more suitable for repair after SCI because it promotes molecular signaling for both CST growth and MEP plasticity.

Integration of mRNA and miRNA Analysis Sheds New Light on the Muscle Response to Heat Stress in Spotted Sea Bass (Lateolabrax maculatus)

Temperature is a crucial environmental factor for fish. Elevated temperatures trigger various physiological and molecular responses designed to maintain internal environmental homeostasis and ensure the proper functioning of the organism. In this study, we measured biochemical parameters and performed mRNA–miRNA integrated transcriptomic analysis to characterize changes in gene expression profiles in the muscle tissue of spotted sea bass (Lateolabrax maculatus) under heat stress. The measurement of biochemical parameters revealed that the activities of nine biochemical enzymes (ALP, γ-GT, AST, GLU, CK, ALT, TG, LDH and TC) were significantly affected to varying degrees by elevated temperatures. A total of 1940 overlapping differentially expressed genes (DEGs) were identified among the five comparisons in the muscle tissue after heat stress. Protein–protein interaction (PPI) analysis of DEGs indicated that heat shock protein genes (HSPs) were deeply involved in the response to heat stress. In addition, we detected 462 differential alternative splicing (DAS) events and 618 DAS genes, which are closely associated with sarcomere assembly in muscle, highlighting the role of alternative splicing in thermal response regulation. Moreover, 32 differentially expressed miRNAs (DEMs) were identified in response to heat stress, and 599 DEGs were predicted as potential target genes of those DEMs, generating 846 DEG–DEM negative regulatory pairs potentially associated with thermal response. Function enrichment analysis of the target genes suggested that lipid metabolism-related pathways and genes were regulated by miRNAs. By analyzing PPIs of target genes, we identified 28 key negative regulatory pairs, including 13 miRNAs (such as lma-miR-122, lma-miR-200b-5p and novel-miR-444) and 15 target genes (such as hspa13, dnaja1, and dnajb1a). This study elucidates the molecular mechanisms of response to high-temperature stress and offers valuable information for the selection and breeding of heat-tolerant strains of spotted sea bass.

Muscle Tissue Response to Vipera berus berus and Vipera berus nikolskii Venoms: A Study on Matrix Metalloproteinases and Cytokine Modulation

Vipera berus, also known as the common adder, is a snake species widely distributed in Europe and parts of Asia. Its venom is a mix of enzymatic and non-enzymatic components causing both local and systemic effects including edema, hemorrhage, myonecrosis, gastrointestinal disorders, and rarely – rhabdomyolysis, coagulopathy and hypovolemic shock. Matrix metalloproteinases (MMPs) and cytokines, being inflammatory mediators, participate both in the development of these reactions and in tissue regeneration after acute damage. The current study was aimed at analyzing the concentrations of important mediators of tissue damage, inflammation and regeneration, namely, MMP-1, -2, -3, -8, -10, TIMP-1 (a tissue inhibitor of MMPs), and pro- and anti-inflammatory cytokines, in rat muscle after intraperitoneal injection of venoms from two subspecies of adders – V. berus berus and V. berus nikolskii — to clarify their role in the local response of skeletal muscle to the studied venoms. Changes in muscle tissue were revealed, namely, significant increase in almost all MMPs including MMP-2, as well as TIMP-1, IFN-γ and anti-inflammatory IL-4 and IL-10 content. Moreover, a tendency for some pro-inflammatory cytokines levels to decline 24 h after venom administration was observed, which may be a sign of inflammation suppression and the beginning of reparative processes associated with extracellular matrix remodeling and formation of an optimal environment for muscle regeneration. However, to establish the exact mechanisms of the changes we found, further studies are needed. The ability of V. berus nikolskii venom to induce more pronounced changes was also shown. Our results may be useful for the development of differentiated and more effective treatment strategies for the consequences of bites by these snakes, which include myonecrosis

Evaluation of Guanidinoacetic Acid Supplementation on Finishing Beef Steer Growth Performance, Skeletal Muscle Cellular Response, and Carcass Characteristics.

This study elucidated the effects of dosage-dependent guanidinoacetic acid (GAA) supplementation on growth performance, muscle responses, and carcass characteristics in finishing beef steers. Thirty crossbred Red Angus beef steers (395 ± 28.09kg) were randomly assigned one of three treatments during a 146-day feedlot study: basal diet without GAA supplementation (CONTROL), 1g of GAA per 100kg of BW daily (LOWGAA), and 2g of GAA per 100kg of BW daily (HIGHGAA). Individual feed intake was monitored daily, growth performance parameters were collected every 28 days, and longissimus muscle (LM) biopsies occurred every 56 days. In biopsied LM, greater (P = 0.048) mRNA expression of IGF-1 was observed in LOWGAA steers on d 112 compared to the CONTROL group. LOWGAA steers also exhibited greater expression of myosin heavy chain (MHC) I compared to CONTROL steers (P < 0.05) and MHC IIA compared to both CONTROL and HIGHGAA treatment groups (P < 0.01) on d 112. GAA supplementation resulted in no change in carcass characteristics, serum and LM tissue metabolites, LM composition, and Warner-Bratzler shear force (WBSF) values (P > 0.05). Data collected from this study demonstrate the influence of GAA supplementation on the gene expression of MHC isoforms and their role in skeletal muscle growth, differentiation, and muscle fiber-typing.

Myosteatosis: diagnostic significance and assessment by imaging approaches.

Myosteatosis has emerged as an important concept in muscle health as it is associated with an increased risk of adverse health outcomes, a higher rate of complications, and increased mortality associated with ageing, chronic systemic and neuromuscular diseases, cancer, metabolic syndromes, degenerative events, and trauma. Myosteatosis involves ectopic infiltration of fat into skeletal muscle, and it exhibits a negative correlation with muscle mass, strength, and mobility representing a contributing factor to decreased muscle quality. While myosteatosis serves as an additional biomarker for sarcopenia, cachexia, and metabolic syndromes, it is not synonymous with sarcopenia. Myosteatosis induces proinflammatory changes that contribute to decreased muscle function, compromise mitochondrial function, and increase inflammatory response in muscles. Imaging techniques such as computed tomography (CT), particularly opportunistic abdominal CT scans, and magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS), have been used in both clinical practice and research. And in recent years, ultrasound has emerged as a promising bedside tool for measuring changes in muscle tissue. Various techniques, including CT-based muscle attenuation (MA) and intermuscular adipose tissue (IMAT) quantification, MRI-based proton density fat fraction (PDFF) and T1-T2 mapping, and musculoskeletal ultrasound (MSUS)-based echo intensity (EI) and shear wave elastography (SWE), are accessible in clinical practice and can be used as adjunct biomarkers of myosteatosis to assess various debilitating muscle health conditions. However, a stan¬dard definition of myosteatosis with a thorough understanding of the pathophysiological mechanisms, and a consensus in assessment methods and clinical outcomes has not yet been established. Recent developments in image acquisition and quantification have attempted to develop an appropriate muscle quality index for the assessment of myosteatosis. Additionally, emerging studies on artificial intelligence (AI) may provide further insights into quantification and automated assessment, including MRS analysis. In this review, we discuss the pathophysiological aspects of myosteatosis, all the current imaging techniques and recent advances in imaging assessment as potential biomarkers of myosteatosis, and the most common clinical conditions involved.

Technical report on intra-operative trigeminal root mapping in percutaneous lesioning for trigeminal neuralgias

PurposePercutaneous lesioning-techniques for treating refractory Trigeminal Neuralgias not amenable to Micro-Vascular Decompression remain useful in neurosurgical practice. Success, avoidance of complications and reduction of side-effects depend on the accurate location of the lesion-maker especially for Radio-Frequency-Thermo-Rhizotomy (RF-Th-Rh).Added to X-ray-guidance, Intra-Operative Neurophysiology can be of significant help to achieve optimal accuracy of the surgery.Based on previous research, this article aims to describe the simplest way to use direct electrical stimulation of the trigeminal root to evoke clinically observable muscle responses allowing to precisely position the tip of the needle for accurate lesioning.Technique to evoke specific localizing muscle responsesMasticatory twitches can be easily produced by stimulating the motor root, through orthodromic conduction to the masticatory muscles.Evoked Muscle Responses (EMRs) can be elicited in the facial nerve territory by stimulating the sensory rootlets, through Trigemino-Facial Reflexes’ pathways (TFRs). Responses in the Orbicularis Oculi is the well-known and readily used “Blink reflex”. On the contrary, TFRs in the lower territory of the facial nerve escaped clinical investigations not having been explored under direct stimulation of the trigeminal root. For both, stimulation at 5 c/s produces better observable twitches (because saccadic) than at 50 c/s which elicits tetanic contractions.ConclusionThe localizing-value of these facial EMRs (associated to evocation of paresthesias) and of the masticatory responses, justifies mapping the trigeminal root before lesioning. Their use could be extended to the other lesioning-techniques: not only Glycerol Neurolysis but also to Balloon Compression (to ascertain location of the trocar at the contact of the TGN inside the Meckel cave) and Open partial Rhizotomies (before deciding to cut the rootlets corresponding to the trigger-zone). This is of importance since lesioning-techniques are needed because not all trigeminal neuralgias are responsive to or even indications of Micro-Vascular Decompression.

Acute acetaminophen ingestion improves the recovery of neuromuscular fatigue following simulated soccer match-play

ObjectiveThis study aimed to investigate the impact of acute acetaminophen (ACT) ingestion on the responses of neuromuscular function, biomarkers of muscle damage, and physical performance during the 72-h recovery period following simulated soccer match-play. DesignThe study followed a crossover randomized, double-blind, placebo-controlled trial design. MethodsDuring the two experimental sessions, thirteen semi-professional male soccer players completed a 90-min simulated soccer match, 60 min after oral ingestion of 1 g ACT or placebo (PL). Maximal voluntary contraction (MVC) and twitch responses of the knee extensors muscles, elicited through electrical femoral nerve stimulation, were utilized to evaluate both peripheral fatigue (potentiated twitch force, Qtw,pot) and central fatigue (voluntary activation, VA). Performance was assessed through countermovement jump (CMJ) and 20 m sprint tests. Creatine kinase (CK) and lactate dehydrogenase (LDH) were also measured. ResultsSmaller reductions were observed in MVC (−13.3 ± 7.5 % vs. -24.7 ± 11.1 %) and VA (−3.8 ± 4.4 % vs. -12.9 ± 5.4 %) in the ACT compared to the PL condition immediately after simulated soccer match-play (p < 0.05). Afterwards, these parameters were recovered 24 h earlier in the ACT session compared to the PL session. Furthermore, the 20 m sprint performance was significantly better throughout the recovery period in the ACT session compared to the PL session. ConclusionThe findings of this study showed that acute ingestion of 1 g of ACT (1 h before exercise) attenuated the decrease in MVC and VA levels after exercise, as well as improved 20 m sprint performance.

Факторна структура підготовленості тхеквондистів 15-17 років

Purpose: to investigate the factor structure of preparedness of taekwondo players of 15-17 years old. Material and Methods. The following methods were used in the research: analysis of scientific and methodical literature, pedagogical testing, medical and biological methods, methods of mathematical statistics. Results: in the course of the research the factor structure of preparedness of taekwondoists of 15-17 years old by the general sample was studied and 9 orthogonal factors were separated in which the sum of loading variables ranges from 9,571 to 1,736, describing 84,804 % of the total variance. The contribution of the first factor, «morpho-functional», to the total variance is 22,788 % and consists of 10 indicators. The second factor accounts for 13,068 % of the total variance, which reflects the special high-speed abilities of taekwondo players of 15-17 years old in the structure of which 7 indicators are included. In the third factor, which accounts for 11,334 % of the total variance, 7 indicators were the main ones. The fourth orthogonal factor has a contribution of 9,259 % of the total variance, the highest correlation was found in 3 indicators. This factor is characterized as a manifestation of coordination abilities with a combination of high-speed endurance (coordination high-speed endurance). The most significant indexes of the fifth factor (6,868 %) are the power index on the left hand (r=0,529) and performance of a side kick with the left (r=0,682) and right (r=-0,569) foot with a deployment on 360° for 15 s. This factor determines the manifestation of strength and the performance of complex coordination kicks and is interpreted by us as «coordination strength». The structure of the sixth factor «Frequency of movements» with a total variance of 6,431 % includes 3 indicators. The seventh factor «ability to control movements» with a total variance of 5,720 % consists of 2 indicators with the highest correlation of lateral kicks with the left foot in the body for 15 s (r=-0,596) and fencing in motion before losing balance with the left foot (r=0,500). The eighth factor «keeping balance»has 2 indicators: fencing for 15 s in the upper level with the left foot (r=0,559) and tilt of a trunk forward from a sitting position (r=-0,514) with a contribution to the general variance of 5,203 %. This is due to the fact that when performing fencing for 15 s in the upper level with the left foot, the athlete stands on one leg and performs blows to the head with the other, to perform this technical technique, the taekwondo player needs a good display of flexibility. The ninth factor reflects reactivity of muscles of hands and has a contribution of 4,133 % of the general dispersion and is characterized by throwing a tennis ball on a distance (r=-0,519). Conclusions. The research has established a dependence between components of preparedness of taekwondo fighters of 15-17 years old, also the most significant factors which reflect morpho-functional indicators, a manifestation of special high-speed abilities, power, coordination and high-speed endurance have been established. With the help of factor analysis, 9 factors were separated, out of 42 considered indicators, the contribution of which is 22,788-4,133 % and is 84,804 % of the total variance. The largest contribution of 22,788 % to the total variance of the sample of taekwondoists of 15-17 years old has morphological and functional indicators.

Astragaloside IV Improves Muscle Atrophy by Modulating the Activity of UPS and ALP via Suppressing Oxidative Stress and Inflammation in Denervated Mice.

Peripheral nerve injury is common clinically and can lead to neuronal degeneration and atrophy and fibrosis of the target muscle. The molecular mechanisms of muscle atrophy induced by denervation are complex and not fully understood. Inflammation and oxidative stress play an important triggering role in denervated muscle atrophy. Astragaloside IV (ASIV), a monomeric compound purified from astragalus membranaceus, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect of ASIV on denervated muscle atrophy and its molecular mechanism, so as to provide a new potential therapeutic target for the prevention and treatment of denervated muscle atrophy. In this study, an ICR mouse model of muscle atrophy was generated through sciatic nerve dissection. We found that ASIV significantly inhibited the reduction of tibialis anterior muscle mass and muscle fiber cross-sectional area in denervated mice, reducing ROS and oxidative stress-related protein levels. Furthermore, ASIV inhibits the increase in inflammation-associated proteins and infiltration of inflammatory cells, protecting the denervated microvessels in skeletal muscle. We also found that ASIV reduced the expression levels of MAFbx, MuRF1 and FoxO3a, while decreasing the expression levels of autophagy-related proteins, it inhibited the activation of ubiquitin-proteasome and autophagy-lysosome hydrolysis systems and the slow-to-fast myofiber shift. Our results show that ASIV inhibits oxidative stress and inflammatory responses in skeletal muscle due to denervation, inhibits mitophagy and proteolysis, improves microvascular circulation and reverses the transition of muscle fiber types; Therefore, the process of skeletal muscle atrophy caused by denervation can be effectively delayed.

Skeletal myocyte-specific knockout of Ptpn1 and Ptpn2 enhances inflammatory response in muscle and increases mortality in polymicrobial sepsis

Abstract Background Critically ill patients often suffer from heart and skeletal muscle atrophy and failure (intensive care unit acquired weakness; ICUAW). Inflammation and sepsis are major risk factors for ICUAW. Critically ill patients with sepsis frequently develop insulin resistance that decreases protein synthesis and increases protein degradation in muscle eventually leading to ICUAW. The link between inflammation and insulin resistance is not well understood, but protein tyrosine phosphatases (PTP), that inhibit insulin signaling via insulin receptor (INSR) dephosphorylation as well as inflammation-associated pathways, are implicated. Hypothesis: We hypothesized that PTP1B and TC-PTP mediate inflammation-induced insulin resistance and muscle atrophy in heart and skeletal muscle. Methods and Results qRT-PCR analyses showed that the proinflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6 caused a ~2-fold increase in Ptpn1/PTP1B and Ptpn2/TC-PTP mRNA expression in C2C12 myocytes as well as in neonatal rat ventricular cardiomyocytes. Inhibition of the IL-6/GP130 pathway by siRNA and inhibitors in myocytes in vitro and skeletal muscle specific gp130 knockout mice in vivo attenuated IL-6-induced Ptpn1/PTP1B and Ptpn2/TC-PTP mRNA expression. CLP-induced polymicrobial sepsis was associated with a significant increase in gene expression and protein content of pro-inflammatory cytokines (Tnf, Il1b, Ifng) and leukocyte markers (CD68, CD11c, F4/80) in muscle of skeletal myocyte specific double knockout (Ptpn1+Ptpn2loxP/loxP, MCK cre, dKO) compared to wildtype (Ptpn1+Ptpn2loxP/loxP) mice in sepsis. This also resulted in a lower survival rate of dKO mice in sepsis (42% WT vs. 23% dKO). Immunohistological analyses revealed centralized nuclei, macrophage/monocyte infiltration and enhanced regeneration (Myh3, Pax7, Ki67) in tibialis anterior muscle of septic dKO mice. A strong activation of the NLRP3-inflammasome, as indicated by cleavage of caspase 1, GSDMD, GSDME and caspase 8, indicative for a pronounced inflammation and activated cell death pathways was observed in muscle of septic dKO mice. Conclusion The proinflammatory cytokine IL-6 increases the expression of Ptpn1 and Ptpn2 and enhances overall PTP activity. Selective inhibition of the IL-6R/GP130 signaling pathway by JAK2- and STAT3-inhibition as well as Gp130 deletion in myocytes in vivo attenuates those effects. Muscle-specific deletion of Ptpn1 and Ptpn2 in skeletal muscle leads to increased mortality, enhanced pro-inflammatory response and induced inflammatory, programmed cell death pathways in sepsis. Our data show that Ptpn1 and Ptpn2 play a key anti-inflammatory role in skeletal muscle.

Coronary microvascular dysfunction in postmenopausal minipigs with multiple risk factors

Abstract Background Coronary microvascular angina occurs in both men and women, however, the majority of patients are postmenopausal women with multiple cardiovascular risk factors, such as diabetes mellitus (DM), chronic kidney disease (CKD) and dyslipidemia. No treatment is available for coronary microvascular dysfunction, requiring more in depth knowledge on the mechanisms underlying this syndrome in this expanding group of patients. Purpose Here we studied microvascular function in vivo and and in vitro in isolated small coronary arteries, in post-menopausal miniswine with multiple cardiovascular risk factors. Methods DM (streptozotocin), hypercholesterolemia (HC, high fat, high sugar diet), CKD (renal artery embolization) and menopause (ovariectomy, OVX) were induced in 5 adult female minipigs (1.5-2 years old, ~40kg, DM+HC+CKD+OVX) for 6 months, while 11 healthy age- and weight-matched female minipigs on normal pig chow served as controls (Normal). At sacrifice, coronary flow reserve (CFR) in response to intracoronary infusion of adenosine was measured under anesthesia. Isolated small coronary arteries were used to study the endothelium-dependent response to bradykinin in the presence and absence of eNOS blockade with LNAME, and cyclooxygenase inhibition by indomethacin, and endothelium-independent response to the nitric oxide (NO) donor, SNAP. Results 6 months of sustained hyperglycemia (17.5±1.0 in DM+HC+CKD+OVX vs 8.2±0.9 mmol/l in Normal, P&amp;lt;0.05 by t-test), hypercholesterolemia (15.4±2.0 vs 1.7±0.1 mmol/l, P&amp;lt;0.05), renal dysfunction (NGAL: 205±72 vs 67±5 ng/ml, P&amp;lt;0.05) and low progesterone levels (13.1±5.7 in DM+HC+CKD+OVX vs 92.0±30.0 nmol/l in Normal, P=0.1) were accompanied by systemic inflammation (TNFα: 62±7 vs 47±1 pg/ml, P&amp;lt;0.05). CFR was significantly reduced in DM+HC+CKD+OVX as compared to the healthy animals (panel A). Coronary small arteries from DM+HC+CKD+OVX animals showed impaired endothelium-dependent vasodilation to bradykinin (panel B), which was mediated by a loss of NO (panels C &amp; D). The loss of NO was partly compensated for by activation of the cyclooxygenase pathway, as indomethacin blunted the dilation to bradykinin in the DM+HC+CKD+OVX animals, but had no effect on the dilation to bradykinin in Normals (panels C &amp; D). Endothelium-independent dilation to SNAP was also impaired in DM+HC+CKD+OVX animals, indicating blunted vascular smooth muscle responsiveness to nitric oxide (panel E). Conclusion Postmenopausal minipigs with multiple risk factors, displayed severe coronary microvascular dysfunction as evidenced by a significantly reduced coronary flow reserve and both reduced NO sensitivity/ production, indicating endothelial and smooth muscle cell dysfunction. Loss of NO-mediated vasodilation was partially compensated by activation of cyclooxygenase pathway. Such perturbations may contribute to reduced myocardial perfusion that is often observed in post-menopausal women with multiple cardiovascular risk factors.

Effects of cervical transcutaneous spinal direct current stimulation on spinal excitability

ObjectiveTo investigate the effects of transcutaneous spinal direct current stimulation (tsDCS) on spinal cord excitability using neurophysiological methods. MethodsSpinal cord motoneuron excitability was assessed using various neurophysiological techniques in a sham-controlled randomized experiment, which involved delivering 2 mA tsDCS and testing four different montages. Transcranial magnetic stimulation (TMS), F-waves to supramaximal ulnar nerve stimulation and somatosensory evoked potentials to upper limb nerves stimulation were measured in the participants with the electrode configuration that yielded the greatest effect, for a total of about 18 min. 18 young volunteers were recruited. ResultsAmong the tested ones, the most promising tsDCS montage was the one with the anode placed on the 7th cervical spinous process and the cathode on the glottis. With this configuration, a significant enhancement of motor responses in the hand muscles to TMS of the contralateral hand motor area was observed during tsDCS (p<0.00001), reaching a plateau after 6 min. This facilitation rapidly declined within a few minutes after the tsDCS was stopped. ConclusionResults of the different techniques suggest a possible contribution to facilitatory neuromodulation of the motoneurons at the cervical spine level. SignificanceThe occurrence of enhanced excitability after tsDCS suggests potential application in individuals with partial corticospinal fiber impairment affecting hand motor function.

First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.

The combined influences of local heat application and resistance exercise on the acute mRNA response of skeletal muscle.

The development and maintenance of the skeletal muscle is crucial for the support of daily function. Heat, when applied locally, has shown substantial promise in the maintenance of the muscle. The purpose of this study was to determine the combined effects of local heat application and acute resistance exercise on gene expression associated with the human muscle growth program. Participants (n = 12, 26 ± 7years, 1.77 ± 0.07m, 79.6 ± 15.4kg, and 16.1 ± 11.6 %BF) completed an acute bilateral bout of resistance exercise consisting of leg press (11 ± 2 reps; 170 ± 37kg) and leg extension (11 ± 1 reps; 58 ± 18kg). Participants wore a thermal wrap containing circulating fluid (40°C, exercise + heat; EX + HT) during the entire experimental period and 4h post-exercise, while the other leg served as an exercise-only (EX) control. Biopsies of the vastus lateralis were collected (Pre, Post, and 4hPost) for gene expression analyses. Intramuscular temperatures increased (Post, +2.2°C ± 0.7°C, and p < 0.001; 4hPost, +2.5°C ± 0.6°C, and p < 0.001) and were greater in the EX + HT leg post-exercise (+0.35°C ± 0.3°C, and p = 0.005) and after 4hPost (+2.1°C ± 0.8°C and p < 0.001). MYO-D1 mRNA was greater in the EX + HT leg vs. the EX (fold change = 2.74 ± 0.42 vs. 1.70 ± 0.28, p = 0.037). No other genes demonstrated temperature sensitivity when comparing both legs (p > 0.05). mRNA associated with the negative regulator, myostatin (MSTN), decreased post-exercise (p = 0.001) and after 4h (p = 0.001). mRNA associated with proteolysis decreased post-exercise (FBXO32, p = 0.001; FOXO3a, p = 0.001) and after 4h (FBXO32, p = 0.001; FOXO3a, p = 0.027). The elevated transcription of the myogenic differentiation factor 1 (MYO-D1) after exercise in the heated condition may provide a mechanism by which muscle growth could be enhanced.

Adaptive responses of skeletal muscle to calcaneal tendon partial injury in rats: insights into remodeling and plasticity.

Skeletal muscle is a highly adaptive tissue, capable of responding to different physiological and functional demands, even in situations that may cause instability. To evaluate how partial calcaneal tendon (CT) injuries affect the remodeling and plasticity of the gastrocnemius muscle over time. The study was carried out with Wistar rats randomly divided into five groups. The control group comprised animals not subjected to partial CT damage. The remaining four groups were subjected to partial CT damage and were further categorized based on the time of euthanasia: 3, 14, 28, and 55 days after injury. The gastrocnemius muscle was collected and used for gene expression analysis, zymography, flow cytometry, and morphology. The calcaneal tendon was analyzed only to verify the presence of the partial injury. The impact of partial CT injury on the gastrocnemius homeostasis, particularly on gene expression, was more pronounced in the 3-day group compared to the other groups, especially the control group. Cytokine profile and morphologic alterations occurred in the 55 days group when compared to the other groups. The data reported here suggest that partial injury can negatively affect intracellular signaling and degradation pathways, disturbing the muscular extracellular matrix regulatory mechanisms and communication with the tendon. However, skeletal muscle seems to mitigate these harmful effects in comparison with lesions that affect muscle and tendon.

Development of a spinopelvic complex finite element model for quantitative analysis of the biomechanical response of patients with degenerative spondylolisthesis.

Research on degenerative spondylolisthesis (DS) has focused primarily on the biomechanical responses of pathological segments, with few studies involving muscle modelling in simulated analysis, leading to an emphasis on the back muscles in physical therapy, neglecting the ventral muscles. The purpose of this study was to quantitatively analyse the biomechanical response of the spinopelvic complex and surrounding muscle groups in DS patients using integrative modelling. The findings may aid in the development of more comprehensive rehabilitation strategies for DS patients. Two new finite element spinopelvic complex models with detailed muscles for normal spine and DS spine (L4 forwards slippage) modelling were established and validated at multiple levels. Then, the spinopelvic position parameters including peak stress of the lumbar isthmic-cortical bone, intervertebral discs, and facet joints; peak strain of the ligaments; peak force of the muscles; and percentage difference in the range of motion were analysed and compared under flexion-extension (F-E), lateral bending (LB), and axial rotation (AR) loading conditions between the two models. Compared with the normal spine model, the DS spine model exhibited greater stress and strain in adjacent biological tissues. Stress at the L4/5 disc and facet joints under AR and LB conditions was approximately 6.6 times greater in the DS spine model than in the normal model, the posterior longitudinal ligament peak strain in the normal model was 1/10 of that in the DS model, and more high-stress areas were found in the DS model, with stress notably transferring forwards. Additionally, compared with the normal spine model, the DS model exhibited greater muscle tensile forces in the lumbosacral muscle groups during F-E and LB motions. The psoas muscle in the DS model was subjected to 23.2% greater tensile force than that in the normal model. These findings indicated that L4 anterior slippage and changes in lumbosacral-pelvic alignment affect the biomechanical response of muscles. In summary, the present work demonstrated a certain level of accuracy and validity of our models as well as the differences between the models. Alterations in spondylolisthesis and the accompanying overall imbalance in the spinopelvic complex result in increased loading response levels of the functional spinal units in DS patients, creating a vicious cycle that exacerbates the imbalance in the lumbosacral region. Therefore, clinicians are encouraged to propose specific exercises for the ventral muscles, such as the psoas group, to address spinopelvic imbalance and halt the progression of DS.

Intravenous Bolus Injection of Fentanyl Triggers an Immediate Central and Upper Airway Obstructive Apnea via Activating Vagal Sensory Afferents.

Intravenous bolus (IVb) injection of fentanyl induces an immediate apnea, but the characteristics of the apnea and relevant mechanism remain unclear. Here, we tested whether IVb injection of fentanyl induced an immediate central and upper airway obstructive apnea associated with chest wall rigidity via activating vagal C-fibers (VCFs) and vagal afferent opioid receptors (ORs). Cardiorespiratory and electromyography of external and internal intercostal, thyroarytenoid and superior pharyngeal constrictor muscles (EMGEI, EMGII, EMGTA and EMGSPC) responses to IVb injection of fentanyl were recorded in anesthetized and spontaneously breathing rats with or without bilateral peri-vagal capsaicin treatment or intra-vagal microinjection of naloxone. Immunohistochemical approach was employed to define the presence of opioid mu-receptor (MOR) expression in vagal C-neurons and a patch clamp technique utilized to determine the evoked current responses of vagal C-neurons to fentanyl in vitro. Fentanyl induced an immediate apnea and subsequent respiratory depression. The apnea was characterized by cessation of EMGEI activity and augmentation of tonic discharges of EMGII, EMGTA, and EMGSPC, i.e., central expiratory apnea, laryngeal closure and pharyngeal constriction/collapse accompanied with chest wall rigidity. The apneic response was abolished by blockade of VCF signal conduction and largely attenuated by antagonism of vagal afferent ORs. The latter significantly alleviated the initial (within 5 min post injection), but not the later, respiratory depression. Vagal C-neurons expressed MORs and were activated by fentanyl. We conclude that IVb injection of fentanyl causes a VCF- and vagal afferent OR-mediated immediate central apnea, upper airway obstruction and chest wall rigidity.