Decrease In Muscle Force Research Articles

Pain hypersensitivity, sensorimotor impairment, and decreased muscle force in a novel rat model of radiation-induced peripheral neuropathy.

Radiation-induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life-long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation-induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model. Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham-radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham-radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain-related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8-week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves. Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non-radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls. A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation-induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition.

Grass-Fed and Non-Grass-Fed Whey Protein Consumption Do Not Attenuate Exercise-Induced Muscle Damage and Soreness in Resistance-Trained Individuals: A Randomized, Placebo-Controlled Trial

Eccentric muscle contractions can cause structural damage to muscle cells resulting in temporarily decreased muscle force production and soreness. Prior work indicates pasture-raised dairy products from grass-fed cows have greater anti-inflammatory and antioxidant properties compared to grain-fed counterparts. However, limited research has evaluated the utility of whey protein from pasture-raised, grass-fed cows to enhance recovery compared to whey protein from non-grass-fed cows. Therefore, using a randomized, placebo-controlled design, we compared the effect of whey protein from pasture-raised, grass-fed cows (PRWP) to conventional whey protein (CWP) supplementation on indirect markers of muscle damage in response to eccentric exercise-induced muscle damage (EIMD) in resistance-trained individuals. Thirty-nine subjects (PRWP, n = 14; CWP, n = 12) completed an eccentric squat protocol to induce EIMD with measurements performed at 24, 48, and 72 h of recovery. Dependent variables included: delayed onset muscle soreness (DOMS), urinary titin, maximal isometric voluntary contraction (MIVC), potentiated quadriceps twitch force, countermovement jump (CMJ), and barbell back squat velocity (BBSV). Between-condition comparisons did not reveal any significant differences (p ≤ 0.05) in markers of EIMD via DOMS, urinary titin, MIVC, potentiated quadriceps twitch force, CMJ, or BBSV. In conclusion, neither PRWP nor CWP attenuate indirect markers of muscle damage and soreness following eccentric exercise in resistance-trained individuals.

Hypochlorous acid exposure impairs skeletal muscle function and Ca2+ signalling: implications for Duchenne muscular dystrophy pathology.

Duchenne muscular dystrophy (DMD) is a fatal X-linked disease characterised by severe muscle wasting. The mechanisms underlying the DMD pathology likely involve the interaction between inflammation, oxidative stress and impaired Ca2+ signalling. Hypochlorous acid (HOCl) is a highly reactive oxidant produced endogenously via myeloperoxidase; an enzyme secreted by neutrophils that is significantly elevated in dystrophic muscle. Oxidation of Ca2+ -handling proteins by HOCl may impair Ca2+ signalling. This study aimed to determine the effects of HOCl on skeletal muscle function and its potential contribution to the dystrophic pathology. Extensor digitorum longus (EDL), soleus and interosseous muscles were surgically isolated from anaesthetised C57 (wild-type) and mdx (dystrophic) mice for measurement of ex vivo force production and intracellular Ca2+ concentration. In whole EDL muscle, HOCl (200μM) significantly decreased maximal force and increased resting muscle tension which was only partially reversible by dithiothreitol. The effects of HOCl (200μM) on maximal force in slow-twitch soleus were lower than found in the fast-twitch EDL muscle. In single interosseous myofibres, HOCl (10μM) significantly increased resting intracellular Ca2+ concentration and decreased Ca2+ transient amplitude. These effects of HOCl were reduced by the application of tetracaine, Gd3+ or streptomycin, implicating involvement of ryanodine receptors and transient receptor potential channels. These results demonstrate the potent effects of HOCl on skeletal muscle function potentially mediated by HOCl-induced oxidation to Ca2+ signalling proteins. Hence, HOCl may provide a link between chronic inflammation, oxidative stress and impaired Ca2+ handling that is characteristic of DMD and presents a potential therapeutic target for DMD. KEY POINTS: Duchenne muscular dystrophy is a fatal genetic disease with pathological mechanisms which involve the complex interaction of chronic inflammation, increased reactive oxygen species production and increased cytosolic Ca2+ concentrations. Hypochlorous acid can be endogenously produced by neutrophils via the enzyme myeloperoxidase. Both neutrophil and myeloperoxidase activity are increased in dystrophic mice. This study found that hypochlorous acid decreased muscle force production and increased cytosolic Ca2+ concentrations in isolated muscles from wild-type and dystrophic mice at relatively low concentrations of hypochlorous acid. These results indicate that hypochlorous acid may be key in the Duchenne muscular dystrophy disease pathology and may provide a unifying link between the chronic inflammation, increased reactive oxygen species production and increased cytosolic Ca2+ concentrations observed in Duchenne muscular dystrophy. Hypochlorous acid production may be a potential target for therapeutic treatments of Duchenne muscular dystrophy.

EMG-informed neuromuscular model assesses the effects of varied bodyweight support on muscles during overground walking

Bodyweight supported walking is a common gait rehabilitation method that can be used as an experimental approach to better understand walking biomechanics. Neuromuscular modeling can provide an analytical means to gain insight into how muscles coordinate to produce walking and other movements. To better understand how muscle length and velocity affect muscle force during overground walking with bodyweight support, we used an electromyography (EMG)-informed neuromuscular model to investigate changes in muscle parameters (muscle force, activation and fiber length) at varying bodyweight support levels: 0%, 24%, 45% and 69% bodyweight. Coupled constant force springs provided a vertical support force while we collected biomechanical data (EMG, motion capture and ground reaction forces) from healthy, neurologically intact participants walking at 1.20 ± 0.06 m/s. The lateral and medial gastrocnemius demonstrated a significant decrease in muscle force (lateral: p = 0.002 and medial: p < 0.001) and activation (lateral: p = 0.007 and medial: p < 0.001) through push-off at higher levels of support. The soleus, in contrast, had no significant change in muscle activation through push-off (p = 0.652) regardless of bodyweight support level even though soleus muscle force decreased with increasing support (p < 0.001). During push-off, the soleus had shorter muscle fiber lengths and faster shortening velocities as bodyweight support levels increased. These results provide insight into how muscle force can be decoupled from effective bodyweight during bodyweight supported walking due to changes in muscle fiber dynamics. The findings contribute evidence that clinicians and biomechanists should not expect a reduction in muscle activation and force when using bodyweight support to assist gait during rehabilitation.

Dilated cardiomyopathy mutation (E525K) in human beta-cardiac myosin enhances actin-activated phosphate release but stabilizes the auto-inhibited super-relaxed state.

Mutations in beta-cardiac myosin (M2β) are a common cause of inherited cardiomyopathies including dilated (DCM) and hypertrophic cardiomyopathy (HCM). We investigated the impact of a DCM mutation (E525K) in the human M2β motor domain, which has been shown to stabilize both the interacting heads motif (IHM) and auto-inhibited super-relaxed (SRX) state via head-tail electrostatic interactions in 15 heptad heavy meromyosin (M2β HMM). These findings suggest E525K may reduce muscle force and power by triggering an increase in the IHM/SRX state. However, it is unclear how E525K impacts the intrinsic motor properties of M2β. Thus, we introduced the mutation into single-headed human cardiac myosin subfragment 1 (M2β-S1), unable to form the IHM, and examined its impact on the ATPase mechanism. We revealed that E525K induces a 2.8-fold increase in maximum steady-state actin-activated ATPase activity (kcat), a 6-fold decrease in the actin concentration at which ATPase is half maximal (KATPase), and a 3.4-fold increase in the fast phase of actin-activated phosphate release. Glutamate 525 is located in the conserved activation loop that is proposed to trigger phosphate release by interacting with the negatively charged N-terminus of actin. We propose the mutation may enhance the rate of rotation of the lower 50-kDa domain, movement of the relay helix/switch II, and lever arm rotation associated with the power stroke. Thus, we will directly examine the impact on the actin-activated power stroke utilizing a FRET approach that measures lever arm rotation. Our results suggest the E525K mutation triggers an increase in intrinsic motor properties, while its ability to stabilize the SRX/IHM state in the myosin dimer likely dominates the molecular mechanism that leads to decreased muscle force and power and DCM pathogenesis.

Force Generation and Muscle Activation of Knee Extensor and Flexor Muscles in Type 2 Diabetes Mellitus Patients.

Type 2 diabetes mellitus (T2DM) is associated with decreased muscle force generation. The disturbed force generation process in T2DM could be attributed to either or both agonist and antagonist muscles activation. The present study aims to assess the effects of T2DM on the interaction of antagonist and agonist muscles in the knee joint. The peak torque, root mean square (RMS) of the SEMG signals, the ratio of torque/RMS, and the interaction of antagonists and agonist muscles were compared between healthy and T2DM patients. Surface ElectroMyoGraphy (SEMG) of knee flexor and extensor muscles were recorded during concentric contraction with an isokinetic dynamometer at 60°/s in 13 T2DM and 12 healthy subjects. The independent sample t-tests were used to compare diabetic and healthy subjects. The significance level was set at 0.05. The antagonist/agonist interaction during maximal extension (P = 0.010) and flexion (P = 0.022) torques of the knee joint showed significantly lower activation of antagonist muscles in T2DM patients than in healthy subjects. Lower knee flexion (41.3%) and extension torques (49.1%) and RMS of agonist and antagonist muscles were observed in T2DM. The torque/RMS ratio (P > 0.05) showed no significant differences in T2DM and healthy subjects. The reduced maximal knee flexor and extensor torques in T2DM are accompanied with the decreased myoelectric activity of corresponding muscles. The related mechanism could be attributed to lower values of antagonist/agonist interaction, which may point out some neural compensatory processes to preserve the functional capacity of the neuromuscular system in T2DM.

Phosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as an AMPK substrate regulating skeletal muscle function

Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.

Reducing the energy cost of walking with low assistance levels through optimized hip flexion assistance from a soft exosuit

As we age, humans see natural decreases in muscle force and power which leads to a slower, less efficient gait. Improving mobility for both healthy individuals and those with muscle impairments/weakness has been a goal for exoskeleton designers for decades. In this work, we discover that significant reductions in the energy cost required for walking can be achieved with almost 50% less mechanical power compared to the state of the art. This was achieved by leveraging human-in-the-loop optimization to understand the importance of individualized assistance for hip flexion, a relatively unexplored joint motion. Specifically, we show that a tethered hip flexion exosuit can reduce the metabolic rate of walking by up to 15.2 ± 2.6%, compared to locomotion with assistance turned off (equivalent to 14.8% reduction compared to not wearing the exosuit). This large metabolic reduction was achieved with surprisingly low assistance magnitudes (average of 89 N, ~ 24% of normal hip flexion torque). Furthermore, the ratio of metabolic reduction to the positive exosuit power delivered was 1.8 times higher than ratios previously found for hip extension and ankle plantarflexion. These findings motivated the design of a lightweight (2.31 kg) and portable hip flexion assisting exosuit, that demonstrated a 7.2 ± 2.9% metabolic reduction compared to walking without the exosuit. The high ratio of metabolic reduction to exosuit power measured in this study supports previous simulation findings and provides compelling evidence that hip flexion may be an efficient joint motion to target when considering how to create practical and lightweight wearable robots to support improved mobility.

65. Pain Hypersensitivity, Sensorimotor Impairment, and Decreased Muscle Force in a Novel Rat Model of Radiation Induced Peripheral Neuropathy

Purpose: Radiation induced peripheral neuropathy is a rare but serious complication often resulting in profound morbidity, life-long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following administration of a clinically relevant radiation dose in a rat model. Methods: Ten rats were randomly assigned to one of two experimental groups: (1) radiation, and; (2) sham-radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into 5 daily doses of 7 Gy/day. Sham-radiated controls were anesthetized and placed in the radiation apparatus, but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of evaluation of walking tracks with calculation of the Sciatic Functional Index (SFI). Pain related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8-week period. At study endpoint, electrophysiological and muscle force assessment were completed, and all sciatic nerves were taken for histomorphometric analysis. Results: Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4-8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non-radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls. Conclusions: A clinically relevant radiation dose of 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation induced peripheral neuropathy can be utilized to assess the effect of pharmacological treatments on this debilitating condition.

Association of acute hepatitis B and acute myopathy: a case report

BackgroundHepatitis B virus infection is a global public health problem. Although hepatitis B virus primarily affects hepatocytes, it sometimes develops disease manifestations outside the liver, such as myopathy, which is commonly caused by chronic hepatitis B.Case presentationThis case report describes a 57-year-old Iranian woman admitted to the hospital with jaundice, fever, body itching, abdominal pain, progressive muscle weakness, icteric sclera, right upper quadrant pain, and decreased muscle force. Examination on the first day of admission revealed that the patient was negative for hepatitis D antibody, positive for hepatitis B core (IgM) antibody, positive for hepatitis B surface antigen, and negative for hepatitis B e antibody but positive for hepatitis B e antigen. Moreover, she showed high levels of hepatitis B virus DNA viral load, creatine kinase, lactate dehydrogenase, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, total bilirubin, direct bilirubin, and alkaline phosphatase, and electromyography/nerve conduction velocity showed acute myopathic process.ConclusionsInterestingly, myopathy symptoms improved after improving hepatitis symptoms and decreasing hepatitis B viral load, suggesting a close association between hepatitis B infection and myopathy.

Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes

Mutations in the BIN1 (Bridging Interactor 1) gene, encoding the membrane remodeling protein amphiphysin 2, cause centronuclear myopathy (CNM) associated with severe muscle weakness and myofiber disorganization and hypotrophy. There is no available therapy, and the validation of therapeutic proof of concept is impaired by the lack of a faithful and easy-to-handle mammalian model. Here, we generated and characterized the Bin1mck-/- mouse through Bin1 knockout in skeletal muscle. Bin1mck-/- mice were viable, unlike the constitutive Bin1 knockout, and displayed decreased muscle force and most histological hallmarks of CNM, including myofiber hypotrophy and intracellular disorganization. Notably, Bin1mck-/- myofibers presented strong defects in mitochondria and T-tubule networks associated with deficient calcium homeostasis and excitation-contraction coupling at the triads, potentially representing the main pathomechanisms. Systemic injection of antisense oligonucleotides (ASOs) targeting Dnm2 (Dynamin 2), which codes for dynamin 2, a BIN1 binding partner regulating membrane fission and mutated in other forms of CNM, improved muscle force and normalized the histological Bin1mck-/- phenotypes within 5weeks. Overall, we generated a faithful mammalian model for CNM linked to BIN1 defects and validated Dnm2 ASOs as a first translatable approach to efficiently treat BIN1-CNM.

Phenotypic features of cancer cachexia-related loss of skeletal muscle mass and function: lessons from human and animal studies.

Cancer cachexia is a complex multi‐organ catabolic syndrome that reduces mobility, increases fatigue, decreases the efficiency of therapeutic strategies, diminishes the quality of life, and increases the mortality of cancer patients. This review provides an exhaustive and comprehensive analysis of cancer cachexia‐related phenotypic changes in skeletal muscle at both the cellular and subcellular levels in human cancer patients, as well as in animal models of cancer cachexia. Cancer cachexia is characterized by a major decrease in skeletal muscle mass in human and animals that depends on the severity of the disease/model and the localization of the tumour. It affects both type 1 and type 2 muscle fibres, even if some animal studies suggest that type 2 muscle fibres would be more prone to atrophy. Animal studies indicate an impairment in mitochondrial oxidative metabolism resulting from a decrease in mitochondrial content, an alteration in mitochondria morphology, and a reduction in mitochondrial metabolic fluxes. Immuno‐histological analyses in human and animal models also suggest that a faulty mechanism of skeletal muscle repair would contribute to muscle mass loss. An increase in collagen deposit, an accumulation of fat depot outside and inside the muscle fibre, and a disrupted contractile machinery structure are also phenotypic features that have been consistently reported in cachectic skeletal muscle. Muscle function is also profoundly altered during cancer cachexia with a strong reduction in skeletal muscle force. Even though the loss of skeletal muscle mass largely contributes to the loss of muscle function, other factors such as muscle–nerve interaction and calcium handling are probably involved in the decrease in muscle force. Longitudinal analyses of skeletal muscle mass by imaging technics and skeletal muscle force in cancer patients, but also in animal models of cancer cachexia, are necessary to determine the respective kinetics and functional involvements of these factors. Our analysis also emphasizes that measuring skeletal muscle force through standardized tests could provide a simple and robust mean to early diagnose cachexia in cancer patients. That would be of great benefit to cancer patient's quality of life and health care systems.

Influence of Obesity on the Organization of the Extracellular Matrix and Satellite Cell Functions After Combined Muscle and Thorax Trauma in C57BL/6J Mice.

Obesity has been described as a major factor of health risk in modern society. Next to intricately linked comorbidities like coronary artery disease or diabetes, an influence of obesity on regeneration after muscle injury has been described previously. However, the influence of obesity on tissue regeneration in a combined trauma, merging the more systemic influence of a blunt lung trauma and the local blunt muscle trauma, has not been investigated yet. Therefore, the aim of this study was to investigate the influence of obesity on regeneration in a mouse model that combined both muscle and thorax trauma. Using gene expression analysis, a focus was put on the structure as well as the organization of the extracellular matrix and on functional satellite cell physiology. An increased amount of debris in the lung of obese mice compared to normal weight mice up to 192 h after combined trauma based on visual assessment can be reported which is accompanied by a decreased response of Mmp2 in obese mice. Additionally, a delayed and elongated response of inhibitor genes like Timp1 has been revealed in obese mice. This elongated response to the trauma in obese mice can also be seen in plasma based on increased levels of pro-inflammatory chemo- and cytokines (IL-6, MCP-1, and IL 23) 192 h post trauma. In addition to changes in the lung, morphological analysis of the injured extensor iliotibialis anticus of the left hind leg in lean and diet-induced obese mice revealed deposition of fat in the regenerating muscle in obese animals hindering the structure of a compact muscle. Additionally, decreased activation of satellite cells and changes in organization and build-up of the ECM could be detected, finally leading to a decreased stability of the regenerated muscle in obese mice. Both factors contribute to an attenuated response to the trauma by obese mice which is reflected by a statistically significant decrease in muscle force of obese mice compared to lean mice 192 h post trauma induction.

Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations.

Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle (EOM) involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for Ryr1 mutations. Ex vivo force production in EOMs from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared with that observed in wild-type, single heterozygous mutant carriers or homozygous RyR1p.A4329D mice. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle-specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the EOM phenotype caused by the RyR1p.Q1970fsX16+p.A4329D compound heterozygous Ryr1 mutations is complex and due to a combination of modifications including a direct effect on the macromolecular complex involved in calcium release and indirect effects on the expression of myosin heavy chain isoforms.

Increased physical activity does not improve obesity-induced decreases in muscle quality in zebrafish (Danio rerio).

Obesity has a negative effect on muscle contractile function, and the effects of obesity are not reversed by weight loss. It is therefore important to determine how muscle function can be restored, and exercise is the most promising approach. We tested the hypothesis (in zebrafish, Danio rerio) that moderate aerobic exercise (forced swimming for 30 min/day, raising metabolic rates to at least twice resting levels) will alleviate the negative effects of obesity on muscle function. We allocated zebrafish randomly to experimental treatments in a fully factorial design with diet treatment [three levels: lean control, diet-induced obese, obese followed by weight loss (obese-lean)], and exercise (exercise and sedentary control) as independent factors. Treatments were conducted for 10 wk, and we measured locomotor performance, isolated muscle mechanics, and myosin heavy chain composition. Obesity led to decreased muscle force production per unit area (P = 0.01), and slowed muscle contraction (P = 0.004) and relaxation rates (P = 0.02). These effects were not reversible by weight loss or exercise. However, at the level implemented in our experimental animals, neither diet nor exercise affected swimming performance or myosin heavy chain concentrations. The moderate levels of exercise we implemented therefore are not sufficient to reverse the effects of obesity on muscle function, and higher intensity or a combination of modes of exercise may be necessary to improve muscle quality during obesity and following weight loss.NEW & NOTEWORTHY Obesity can have a negative effect on muscle function and thereby compromise mobility. Even though aerobic exercise has many physiological benefits in obese and normal-weight individuals, we show that in zebrafish aerobic exercise does not improve obesity-induced reductions in muscle contractile function. A combination between different modes of exercise may be more effective than aerobic exercise alone.

Diffusion tensor imaging and diffusion modeling: Application to monitoring changes in the medial gastrocnemius in disuse atrophy induced by unilateral limb suspension.

Diffusion tensor imaging (DTI) assesses underlying tissue microstructure, and has been applied to studying skeletal muscle. Unloading of the lower leg causes decreases in muscle force, mass, and muscle protein synthesis as well as changes in muscle architecture. To monitor the change in DTI indices in the medial gastrocnemius (MG) after 4-week unilateral limb suspension (ULLS) and to explore the feasibility of extracting tissue microstructural parameters based on a two-compartment diffusion model. Prospective cohort study. Seven moderately active subjects (29.1 ± 5.7 years). 3T, single-shot fat-suppressed echo planar spin echo sequence. Suspension-related changes in the DTI indices (eigenvalues: λ1 , λ2 , λ3 , fractional anisotropy; coefficient of planarity) were statistically analyzed. Changes in model-derived tissue parameters (muscle fiber circularity and diameter, intracellular volume fraction, and residence time) after suspension are qualitatively discussed. Changes in the DTI indices of the MG between pre- and postsuspension were assessed using repeated-measures two-way analysis of variance (ANOVA). All the eigenvalues (λ1 : P = 0.025, λ2 : P = 0.035, λ3 : P = 0.049) as well as anisotropic diffusion coefficient (P = 0.029) were significantly smaller post-ULLS. Diffusion modeling revealed that fibers were more circular (circularity index increased from 0.55 to 0.95) with a smaller diameter (diameter decreased from 82-60 μm) postsuspension. We have shown that DTI indices change with disuse and modeling can relate these voxel level changes to changes in the tissue microarchitecture. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

Deficiency of MTMR14 impairs male fertility in Mus musculus.

Calcium signalling is critical for successful fertilization. In spermatozoa, capacitation, hyperactivation of motility and acrosome reactions are all mediated by increases in intracellular Ca2+. Our previous reports have shown that deficiency of MTMR14, a novel phosphoinositide phosphatase, induces a muscle disorder by disrupting Ca2+ homeostasis. Recently, we found that MTMR14 is also expressed in the testes; however, whether deficiency of MTMR14 in the testes also alters the Ca2+ concentration and impairs male fertility remains entirely unknown. In the present study, we found that MTMR14 is also expressed in the testes and mature sperm cells, suggesting that deficiency of MTMR14 might have some effect on male fertility. Both in vivo fertility and in vitro fertilization tests were then performed, and we found that MTMR14-/- male mice showed decreased fertility. A series of experiments were then arranged to test the testis and sperm parameters; we found that MTMR14 deficiency caused small size of the testes, small numbers of both total and immotile sperm, expanded membrane of sperm tail, a decreased proportion of acrosome reaction, and in contrast, an increased proportion of abnormal sperm and augmented apoptosis, etc. Further study also found that the muscle force of the vas deferens decreased significantly in KO mice. Intracellular calcium homeostasis in the testes and epididymis was impaired by MTMR14 deletion; moreover, the relative mRNA expression levels of Itpr1, Itpr2, and Ryr3 were dramatically decreased in MTMR14 KO mice. Thus, MTMR14 deletion impairs male fertility by causing decreased muscle force of the vas deferens and intracellular calcium imbalance.

Acidosis affects muscle contraction by slowing the rates myosin attaches to and detaches from actin.

The loss of muscle force and power during fatigue from intense contractile activity is associated with, and likely caused by, elevated levels of phosphate ([Formula: see text]) and hydrogen ions (decreased pH). To understand how these deficits in muscle performance occur at the molecular level, we used direct measurements of mini-ensembles of myosin generating force in the laser trap assay at pH 7.4 and 6.5. The data are consistent with a mechanochemical model in which a decrease in pH reduces myosin's detachment from actin (by slowing ADP release), increases non-productive myosin binding (by detached myosin rebinding without a powerstroke), and reduces myosin's attachment to actin (by slowing the weak-to-strong binding transition). Additional support of this mechanism is found by incorporating it into a branched pathway model for the effects of [Formula: see text] on myosin's interaction with actin. Including pH-dependence in one additional parameter (acceleration of [Formula: see text]-induced detachment), the model reproduces experimental measurements at high and low pH, and variable [Formula: see text], from the single molecule to large ensemble levels. Furthermore, when scaled up, the model predicts force-velocity relationships that are consistent with muscle fiber measurements. The model suggests that reducing pH has two opposing effects, a decrease in attachment favoring a decrease in muscle force and a decrease in detachment favoring an increase in muscle force. Depending on experimental details, the addition of [Formula: see text] can strengthen one or the other effect, resulting in either synergistic or antagonistic effects. This detailed molecular description suggests a molecular basis for contractile failure during muscle fatigue.

Challenging the Cinderella Hypothesis: A New Model for the Role of the Motor Unit Recruitment Pattern in the Pathogenesis of Myofascial Pain Syndrome in Postural Muscles.

BackgroundThe energy crisis hypothesis, which is a widely accepted model for the pathogenesis of myofascial pain, has been corroborated by experimental observations. However, the nature of the insult leading to the energy crisis remains elusive. A commonly cited model for this insult is the Cinderella hypothesis, suggesting that hierarchical recruitment of motor units leads to a disproportional load on small units, thus driving them towards an energy crisis. New findings cast doubt on this model, showing that in postural muscles motor units are recruited in rotation, rather than in a hierarchical order, precluding the formation of the so-called Cinderella units.ObjectiveTo explore the influence of common myofascial predisposing factors such as muscle load and muscle strength on the relaxation time of postural muscle motor units, assuming they are recruited in rotation.MethodsA stochastic model of a postural skeletal muscle was developed which integrates the energy crisis model and motor unit rotation patterns observed in postural muscles. Postulating that adequate relaxation time is essential for the energetic replenishment of motor units, we explored the influence of different parameters on the relaxation time of individual motor units under varying conditions of muscle loads and muscle strengths.ResultsThe motor unit relaxation/contraction time ratio decreases with elevated muscle loads and with decreased total muscle strength.ConclusionsIn a model of a postural muscle, in which motor units are recruited in rotation, common predisposing factors of myofascial pain, such as increased muscle load and decreased muscle force, lead to shortened motor unit relaxation periods.

P.318 - AT-300, a calcium modulator, improves muscle force production and decreases muscle degeneration in D2-mdx model of Duchenne muscular dystrophy

AT-300 is a peptide, a new class of drugs that selectively modulate mechanosensitive cation channels. These channels are involved in disease progression in DMD and murine models. The objective of these investigations was to determine AT-300 1)PK in mouse muscle and 2) acute and 6 weeks in vivo efficacy in the D2-mdx. PK and efficacy testing were conducted on DBA/2J and D2-mdx murine model of DMD at 6–9 weeks of age. Efficacy was measured in situ with a muscle lever system. Isometric torque after 20 eccentric contractions of the hind limb plantar flexors was compared to baseline and to controls. Muscle was evaluated with Evans Blue dye as an indicator of sarcolemmal damage. Additionally, histological analysis was performed to determine numbers of central nuclei, muscle cell morphometry and quantitation of fibrosis. Skeletal and cardiac muscle concentrations increased with increasing dosage, time and exercise activity. Target concentration was readily achieved within 7 days. Kidney concentrations were high and appeared to saturate at higher dosage and activity levels. There was a very low brain concentration. AT-300 showed a much higher affinity for binding sites in the tissue (possibly membrane association) than to serum protein and resistance to enzymatic digestion. AT-300 protects skeletal muscle to EC injury by ~50% compared to the untreated group. Body weight loss was significantly less in treated vs. control mice after 6 weeks treatment, also showing preservation of muscle fiber cross-sectional area. AT-300 partially prevented muscle force drop after eccentric contraction. There was no difference in treated mice on EBD incorporation, central nucleation, and interstitial fibrosis. AT-300 protects against decrease muscle force loss in vivo caused by eccentric contraction injury and reduces muscle degeneration. Longer studies are needed to assess the full effects of AT-300 in dystrophic muscle.