Skeletal Muscle Fatigability Research Articles

Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis.

Myasthenia Gravis (MG) is a chronic disabling autoimmune disease caused by autoantibodies to the neuromuscular junction (NMJ), characterized clinically by fluctuating weakness and early fatigability of ocular, skeletal and bulbar muscles. Despite being commonly considered a prototypic autoimmune disorder, MG is a complex and heterogeneous condition, presenting with variable clinical phenotypes, likely due to distinct pathophysiological settings related with different immunoreactivities, symptoms' distribution, disease severity, age at onset, thymic histopathology and response to therapies. Current treatment of MG based on international consensus guidelines allows to effectively control symptoms, but most patients do not reach complete stable remission and require life-long immunosuppressive (IS) therapies. Moreover, a proportion of them is refractory to conventional IS treatment, highlighting the need for more specific and tailored strategies. Precision medicine is a new frontier of medicine that promises to greatly increase therapeutic success in several diseases, including autoimmune conditions. In MG, B cell activation, antibody recycling and NMJ damage by the complement system are crucial mechanisms, and their targeting by innovative biological drugs has been proven to be effective and safe in clinical trials. The switch from conventional IS to novel precision medicine approaches based on these drugs could prospectively and significantly improve MG care. In this review, we provide an overview of key immunopathogenetic processes underlying MG, and discuss on emerging biological drugs targeting them. We also discuss on future direction of research to address the need for patients' stratification in endotypes according with genetic and molecular biomarkers for successful clinical decision making within precision medicine workflow.

Time-of-day does not impact skeletal muscle contractile function, fatigability, or contraction-stimulated glucose uptake

Time-of-day impacts different aspects of mammalian physiology, such as the sleep/wake cycle, blood pressure, and body temperature. These time-of-day changes, or “circadian cycles”, are regulated by a central clock in the central suprachiasmatic nucleus of the hypothalamus and peripheral clocks located in other tissues, such as the liver, heart, and skeletal muscle. Interestingly, a growing body of data suggests that exercise performance and capacity also vary by time-of-day, with chronobiological effects on skeletal muscle metabolism and contractile function (i.e., force production) being proposed as important mediators. However, to date, no studies have specifically investigated the effect of time-of-day on skeletal muscle contractile function or glucose metabolism. The objective of this work was to assess ex vivo skeletal muscle contractile function, fatigability, and contraction-stimulated glucose uptake in the extensor digitorum longus (EDL) and soleus from 13-week-old female C57BL/6NJ mice at four different times-of-day (Light cycle time-points: Zeitgeber Time [ZT] ZT1 and ZT7; Dark cycle time-points: ZT13 and ZT19). We used an ex vivo approach as it allowed us to study skeletal muscle in isolation, and thus, independent of other factors that might influence contractile function or glucose metabolism (e.g., nerve function, humoral factors, etc.). We hypothesized that skeletal muscle contractile function, fatigability and contraction-stimulated glucose uptake would not be different by time-of-day. To control for meal-timing, mice were orally gavaged with dextrose (2 g/kg) and then fasted (3 hours) before contractile testing, which consisted of a force-frequency test (1-120 Hz, 0.3 ms pulse, 35 volts; 300 ms and 400 ms train for EDL and soleus, respectively) followed by a 15 minute fatigue test in which the muscles were repeatedly stimulated (EDL: 100 Hz stimulation every 15 seconds; Soleus: 30 Hz stimulation every 2 seconds). Glucose uptake was measured during the fatigue test using the [3H]-2-deoxyglucose (2DOG) uptake approach, with the contralateral muscle being the rested control. Significantly, contractile function, including peak twitch tension and maximal tetanic tension (EDL — ZT1: 281±13; ZT7: 300±21; ZT13: 261±28; ZT19: 280±40 kPa, P = 0.7661, one-way ANOVA; Soleus — ZT1: 117±16; ZT7: 115±18; ZT13: 117±11; ZT19: 111±10 kPa, P = 0.9923, one-way ANOVA) were not different by time-of-day. Similarly, fatigability, as measured as the tension·time integral during the 15 min fatigue test was not different by time-of-day (EDL — ZT1: 640±89; ZT7: 686±92; ZT13: 708±110; ZT19: 683±142 kPa·min, P = 0.9803, one-way ANOVA; Soleus — ZT1: 245±42; ZT7: 261±35; ZT13: 200±41; ZT19: 244±34 kPa·min, P = 0.7019, one-way ANOVA). Finally, while contraction significantly increased 2DOG uptake above basal by ~1.6-fold and ~1.8-fold in the soleus and EDL, respectively, this increase was not different by time-of-day. Taken together, these results demonstrate that time-of-day does not impact skeletal muscle contractile function, fatigability, or contraction-stimulated glucose uptake, regardless of muscle type. By extension, skeletal muscle, per se, is unlikely to be a contributing factor to the documented effects of time-of-day on whole-body exercise performance. This was funded by the UC San Diego Medical Scientist Training Program and NIH R21 AG067495. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

GOOD OUTCOMES OF OCULAR MYASTHENIA GRAVIS IN A YOUNG ADULT MALE: A CASE REPORT

Abstract
 Introduction : Myasthenia gravis (MG) is characterized by fluctuating weakening and fatigability of skeletal muscles. Ocular MG (OMG) occurs when the symptoms of MG are limited to the ocular muscles.
 Case Illustration : A 21-year-old male presents with a two-month history of drooping both eyelids. The drooping eyelids improved in the morning or after a nap, and got worse in the evening. Ocular examination revealed limitation towards all gazes with bilateral ptosis. Visual acuity, anterior segment, visual fields, slit lamp, and fundus examinations were unremarkable. The ice pack and rest test resulted in a significant improvement after two minutes of ice pack application and 30-minute rest, raising suspicion for the diagnosis of MG. Acetylcholine receptor antibody (AChR) test was positive for AChR binding antibody. Treatment for OMG is initiated with an oral acetylcholinesterase inhibitor, pyridostigmine, and corticosteroid. The ptosis and ophthalmoplegia improved after one week follow- up and recovered completely after eight weeks of follow-up.
 Discussion : The hallmarks of MG are fluctuating fatigable muscle weakness that worsen with activity and improve on rest. Neurological exam and clinical neurological history are essential to establish the diagnosis. Bedsite tests, electrophysiologic test, and the antibody test all support the clinical diagnosis of MG.
 Conclusion : OMG progresses to its generalized form 90% of the time during the first two years of the onset of ocular symptoms. Early detection and prompt treatment are the key which may help to prevent or minimize the occurrence of myasthenia crisis.

Fatigue as hallmark of Fabry disease: role of bioenergetic alterations.

Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The "metabolic hypothesis" to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged. In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.

Critical Understanding of Myasthenia Gravis on the Basis of Vyadhi Ghatak

Myasthenia gravis (MG) is an autoimmune neuromuscular junction (NMJ) disorder characterized by weakness and fatigability of skeletal muscles. Myasthenia gravis has prevalence as high 200 in 100,000. It affects individuals in all age groups, but peak incidences occur in women in their twenties and thirties and in men in their fifties and sixties. Overall, women are affected more frequently than men, in a ratio of 3:2. It has bimodal age distribution. In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. It presents with fluctuating skeletal muscle weakness and fatigue most commonly affecting the ocular muscles, although any muscle may be affected. In modern science treatment of Myasthenia gravis include anti-cholinesterase medications, glucocorticoids and other immunosuppressive agents. Long term use of steroid and immune modulator drugs has many adverse effects on other system of body. Ayurvedic therapies can give much more promising results. Comparison between myasthenia gravis and diseases explained in Ayurveda is difficult and exact correlation is not possible. But based on critical understanding of Vyadhighataka, a probable diagnosis can be made and treated accordingly. In this article, attempt is made to understand the pathogenesis of myasthenia gravis by considering the concepts of Dosha (vitiated Dosha), Dushya (vitiated Dushya), Aama, Agnimandya, and Srotovaigunya. For any disease pathology to begin, all components must be present. Pathogenesis of any disease will not occur without these elements.

Prior Alcohol Use does not Enhance Skeletal Muscle Atrophy and Force Decrements Induced by Cancer Cachexia

Introduction/objectiveAlcohol (EtOH) is a well‐known myotoxin with up to 60% of alcoholics suffering from alcoholic myopathy, characterized by progressive weakening and atrophy of proximal muscles. EtOH consumption is also associated with increased risk of cancer and continued EtOH intake enhances a primary comorbidity of cancer, cancer cachexia, or the loss of skeletal muscle strength and mass. However, the effects of prior EtOH use on cancer cachexia remains unknown. Therefore, the study objective was to determine if the cessation of EtOH prior to cancer development influences skeletal muscle force production, fatigability, and twitch characteristics.HypothesisWe hypothesize that discontinuing EtOH use prior to cancer progression will have no effect on skeletal muscle force production in tumor bearing mice.MethodsMale CD2F1 mice acclimated to a non‐EtOH containing Lieber DeCarli liquid diet for one week. Then, the concentration of EtOH was increased to 20% EtOH kcal/day for 6 weeks in EtOH mice. Mice then returned to non‐EtOH containing diet and C26 colon cancer cells were inoculated into the right flank of cancer groups. After 2‐3 weeks of cancer development muscle function was assessed. Mice were anesthetized, with the distal tendon of the lower leg attached to a servomotor, stimulating the posterior crural muscle complex by percutaneous electrodes. Peak isometric force was taken at 100 Hz, while fatigability was assessed using 60 isometric contractions produced over 4‐mins given at 100 Hz, and fatigue recovery measured using 100 Hz stimulations at 5‐ and 10‐minutes later. Triceps surae complex was excised and weighed following the force protocol.ResultsCancer reduced triceps surae muscle weight in both control and EtOH consuming mice (p < 0.0001). Cancer reduced force production (p= 0.009) of 100 Hz tetanic stimulation while no further effect of EtOH was observed. Main effects of C26 (p< 0.0001) were observed for fatigue within both diets, revealing reduced force production and increased fatigue. Force production was decreased across the fatigue protocol in all groups (p< 0.0001), while main effects of C26 (p<0.0001) were observed within the control and EtOH diets, revealing similarly reduced force production and increased fatigue regardless of EtOH status. Fatigue recovery was also similar across all groups. Twitch half relaxation was increased in C26 mice (p= 0.0283), showing a disruption in relaxation that is cancer dependent and not exacerbated by EtOH. No changes in twitch maximum force or rate of force development were noted between groups.ConclusionsTumor‐bearing mice produced less force during a tetanic stimulation and fatigue protocol, in accordance with significant muscle atrophy of the triceps surae. The prior consumption of EtOH did not worsen cancer‐induced deficits in skeletal muscle contraction. As it has been shown previously that the continuation of EtOH throughout the progression of cancer enhances cancer cachexia, these data exemplify the clinical benefits of stopping EtOH consumption as early as possible.

Physiological and molecular sex differences in human skeletal muscle in response to exercise training.

Sex differences in exercise physiology, such as substrate metabolism and skeletal muscle fatigability, stem from inherent biological factors, including endogenous hormones and genetics. Studies investigating exercise physiology frequently include only males or do not take sex differences into consideration. Although there is still an underrepresentation of female participants in exercise research, existing studies have identified sex differences in physiological and molecular responses to exercise training. The observed sex differences in exercise physiology are underpinned by the sex chromosome complement, sex hormones and, on a molecular level, the epigenome and transcriptome. Future research in the field should aim to include both sexes, control for menstrual cycle factors, conduct large-scale and ethnically diverse studies, conduct meta-analyses to consolidate findings from various studies, leverage unique cohorts (such as post-menopausal, transgender, and those with sex chromosome abnormalities), as well as integrate tissue and cell-specific -omics data. This knowledge is essential for developing deeper insight into sex-specific physiological responses to exercise training, thus directing future exercise physiology studies and practical application.

MYASTHENIA GRAVIS IN PREGNANCY: A RARE ASSOCIATION WITH AN UNPREDICTABLE EVOLUTION – THREE CASES PRESENTATION

Myasthenia gravis is a neuro-immunological disease due to the blockage of motor plate post-synaptic receptors by antiacetylcholine receptors antibodies, causing excessive fatigability of skeletal striated muscles. Thus, vital prognosis is engaged by swallowing disorders and respiratory distress related to pharyngeal striated and intercostal muscles damage. Myasthenia evolves by flare-ups, with two peaks of prevalence: first one, between 20 and 30 years-old with femal predominance. Then after 40 years-old, sex ratio evens out. Therefore, association of myasthenia and pregnancy is not exceptional, hence the interest in knowing particularities of these pregnancies, to ensure optimal monitoring for both mother and child. Indeed, mother’s risk is myasthenia decompensation, while child’s risk is neonatal myasthenia gravis. We report three myasthenia and pregnancy cases, from prenatal period to pueripartum, then we discuss in literature light, myasthenia gravis bidirectional influence on pregnancy, as well as impact of anti-myasthenic treatments on pregnancy.

Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model

Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1−/−) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1−/− resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1−/− resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.

Anesthetic implications in patients with myasthenia gravis undergoing spine surgery

Myasthenia gravis is a chronic autoimmune disorder affecting post-synaptic neuromuscular junction. It is characterized by skeletal muscle weakness and fatigability which improves with rest. The anesthesiologists may encounter these patients for thymectomy or sometimes for incidental surgeries. However, it is a real challenge for anesthesiologists because of the unpredictable response with muscle relaxants and analgesics and the possibility of ventilatory complications. In the present case report, we report the management of a 52-year-old female patient with myasthenia gravis who is posted for schwannoma surgery.

Anaesthetic Management of a Patient with Myasthenia Gravis Posted for Tonsillectomy- A Case Report

Myasthenia gravis is a chronic autoimmune disease of neuromuscular junction which causes skeletal muscle weakness and fatigability, characterised by decrement in postsynaptic acetylcholine receptor at neuromuscular junction caused by auto-antibodies destruction. There are three types of myasthenia gravis in children- transient neonatal, congenital and juvenile. Juvenile Myasthenia Gravis (JMG) is an autoimmune disorder that can affect the all skeletal muscles including extraocular muscles, which may lead to fatigability and generalised weakness. This report is about a case of seven-year-old patient weighing 25 kg presented with throat pain since one and half month. Patient was a known case of congenital myasthenia gravis and diagnosis was confirmed by Edrophonium test. He underwent tonsillectomy and was successfully managed under general anaesthesia with no muscle relaxant technique. Tonsillectomy in paediatric patients is not an uncommon surgical procedure. In spite of being a common surgery, it is still challenging to the surgeon as well as the anaesthesiologist as there is a shared airway between the two. Also, in the postoperative period there are chances of post-tonsillectomy bleeding causing airway obstruction, if not diagnosed and treated early could risk the life of the patient. Therefore, this surgery poses an increased risk of mortality and morbidity.

Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management.

Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction, characterized by skeletal muscle weakness and fatigability. It is caused by autoantibodies targeting proteins of the neuromuscular junction; ~85% of MG patients have autoantibodies against the muscle acetylcholine receptor (AChR-MG), whereas about 5% of MG patients have autoantibodies against the muscle specific kinase (MuSK-MG). In the remaining about 10% of patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG). Since serological tests are relatively easy and non-invasive for disease diagnosis, the improvement of methods for the detection of known autoantibodies or the discovery of novel autoantibody specificities to diminish SN-MG and to facilitate differential diagnosis of similar diseases, is crucial. Radioimmunoprecipitation assays (RIPA) are the staple for MG antibody detection, but over the past years, using cell-based assays (CBAs) or improved highly sensitive RIPAs, it has been possible to detect autoantibodies in previously SN-MG patients. This led to the identification of more patients with antibodies to the classical antigens AChR and MuSK and to the third MG autoantigen, the low-density lipoprotein receptor-related protein 4 (LRP4), while antibodies against other extracellular or intracellular targets, such as agrin, Kv1.4 potassium channels, collagen Q, titin, the ryanodine receptor and cortactin have been found in some MG patients. Since the autoantigen targeted determines in part the clinical manifestations, prognosis and response to treatment, serological tests are not only indispensable for initial diagnosis, but also for monitoring treatment efficacy. Importantly, knowing the autoantibody profile of MG patients could allow for more efficient personalized therapeutic approaches. Significant progress has been made over the past years toward the development of antigen-specific therapies, targeting only the specific immune cells or autoantibodies involved in the autoimmune response. In this review, we will present the progress made toward the development of novel sensitive autoantibody detection assays, the identification of new MG autoantigens, and the implications for improved antigen-specific therapeutics. These advancements increase our understanding of MG pathology and improve patient quality of life by providing faster, more accurate diagnosis and better disease management.

The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

The face of myasthenia gravis.

Myasthenia gravis (MG) is characterized by fluctuating weakness and fatigability of skeletal muscles. In most patients, extraocular and bulbar muscles are affected first, leading to diplopia, ptosis, and weakness of facial muscles.1 We recorded the faces of 38 healthy controls and 52 patients with MG while performing a standardized set of facial expressions. These images were averaged using Python version 3.8.0. This resulted in highly similar faces with no recognizable individual features. The only discernible differences are typical clinical hallmarks of the disease: ptosis and generalized facial weakness around the eyes and mouth resulting in less vivid facial expression (figure).

The Effect of Wheel Exercise on Functional Indices of Cachexia in Tumor-bearing Mice.

Cancer-related fatigue and muscle wasting have received significant attention over the last few decades with the goal of establishing interventions that can improve cancer patient life quality and survival. Increased physical activity has shown to reduce cancer-associated fatigue and has been proposed as a promising therapeutic to attenuate cancer-induced wasting. However, significant gaps remain in our understanding of how physical activity affects the compositional and functional changes that initiate muscle wasting. The purpose of the current study was to determine the effect of wheel exercise on body composition and functional indices of cancer cachexia before the development of significant wasting. Thirteen-week-old male Apc (MIN) and C57BL/6 (B6) mice were given free wheel access (W) or a locked wheel (Sed) for 5 wk. Wheel activity was reduced in the MIN compared with B6; however, wheel access increased complex II expression in isolated skeletal muscle mitochondria regardless of genotype. Wheel access had no effect on tumor burden or plasma interleukin-6 in the MIN. MIN-W increased body weight and lean mass compared with MIN-Sed, and there was a direct correlation between wheel distance and lean mass change. MIN-W increased grip strength and treadmill time to fatigue compared with MIN-Sed. Within MIN-W mice, skeletal muscle fatigability was only improved in high runners (>60 min·d). Our results suggest that there were therapeutic benefits of increased activity related to body composition, behavior, and whole-body function that were not dependent on exercise duration; however, there was an exercise threshold needed to improve skeletal muscle fatigability in tumor-bearing mice. Interestingly, wheel access was able to improve compositional and functional outcomes without mitigating tumor number or size.

Long-term outcome of cats with acquired myasthenia gravis without evidence of a cranial mediastinal mass.

BackgroundAcquired myasthenia gravis (AMG) is increasingly recognized in cats, yet information regarding the natural history of the disease, treatment, and outcome including occurrence of immune and spontaneous remission remains limited.ObjectiveTo determine the long‐term outcome of cats with AMG without evidence of a cranial mediastinal mass (CMM).AnimalsEight cats diagnosed with AMG without evidence of a CMM.MethodsRetrospective case series. The medical records of cats diagnosed with AMG between 2005 and 2018 from 2 veterinary referral hospitals were reviewed for inclusion. Inclusion criteria consisted of a diagnosis of AMG, thoracic imaging, serum biochemistry including measurement of creatine kinase, and a CBC. Exclusion criteria were the presence of an identifiable CMM, or administration of methimazole or carbimazole.ResultsAll cats had an excellent long‐term outcome, achieving immune remission within 6 months of diagnosis, including 4 cats that did not receive any treatment and whose natural course of disease involved spontaneous remission. Clinical presentation was heterogeneous, and skeletal muscle weakness and fatigability induced or exacerbated by the wheelbarrow exercise stress test were the most consistent abnormalities associated with AMG.Conclusion and Clinical ImportanceCats diagnosed with AMG without evidence a CMM have a favorable outcome and frequently achieve immune remission. Moreover, the natural history of AMG in cats includes spontaneous remission when there is no evidence of a CMM. Attempting to rule out the presence of a CMM therefore refines prognosis, and treatment is not always necessary in this disease population.

Lactobacillus rhamnosus GG improves skeletal muscle fatigability in a mouse model of hyperhomocysteinemia

Hyperhomocysteinemia (HHcy) can occur due to insufficiency in cystathionine‐β‐synthase (CBS), activity causing skeletal muscle fatigability however it is still unclear whether this effect is mediated via reduced intracellular calcium release or lower ATP production or both. Consumption of Lactobacillus rhamnosus GG (LGG) as a probiotic supplementation has been shown to improve overall exercise performance and the physical strength. Based on this understanding, we hypothesized that LGG administration might improve the muscle functions in a mouse model of HHcy via improving the calcium release from the sarcoplasmic reticulum (SR) compartment and thus inducing the ATP production in the muscle tissue. To study this we used 4 experimental groups of mice as follows: Group‐I: WT mice (C57BL/6J); Group‐II: genetically heterozygous CBS deficient mice (CBS+/−) + High Methionine Diet (HMD), Group‐III: CBS+/− + HMD + LGG (orally @ 2.5x105 CFU/d for 12 weeks), and Group‐IV: WT + LGG. Data revealed that CBS mice had significantly high tHcy levels, and lower body weight in comparison to the age‐matched WT mice, unlike the LGG treated CBS+/− mice. Whole animal muscle fatigability measurements (by swim‐test performance and grip strength test) showed that HHcy induced muscle fatigability in CBS+/− mice compared to WT mice and it was noticed that LGG supplementation was able to improve this effect. Moreover, when we measured the excitation‐contraction coupling via muscle myobath experiment, we found that the soleus muscle of CBS mice produced lower contraction force and showed longer relaxation duration as compared to the WT mice, and these effects were also seemed to be mitigated via LGG consumption. Finally, we found reduced ATP production and calcium release were also improved in the CBS mice group by LGG supplementation. In conclusion, this work highlights the therapeutic potential of LGG towards reversing the harmful metabolic effects of HHcy mediated skeletal muscle dysfunction.Support or Funding InformationNIH (HL‐74815, HL‐139047, AR071789)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Skeletal Muscle Fatigability in Heart Failure.

Evidence suggests that heart failure (HF) patients experience skeletal muscle fatigability in the lower extremity during single-limb tasks. The contribution of skeletal muscle fatigability to symptoms of exercise intolerance (perceived fatigue and dyspnea) is relatively unclear. Symptomatic or ‘perceived’ fatigue is defined by the sensations of exhaustion or tiredness that patients experience either at rest or while performing a motor task. Although factors that contribute to symptoms of fatigue in patients with HF are multifactorial; the skeletal muscle likely plays a major role. Skeletal muscle fatigability, as opposed to symptomatic fatigue, is an objective measure of a reduction in muscle force or power or reduced ability of the muscles to perform over time. Indeed, evidence suggests that patients with HF experience greater skeletal muscle fatigability which may contribute to a diminution in motor performance and the overall symptomatology that is hallmark of exercise intolerance in HF. This review will discuss (1) skeletal muscle fatigability in patients with HF, (2) the mechanisms contributing to locomotor skeletal muscle fatigability in HF and (3) the relationship of fatigability to symptoms of perceived fatigue and exercise intolerance in HF patients. Evidence suggests that cardiac dysfunction alone does not contribute to exercise intolerance. Therefore, mechanisms of skeletal muscle fatigability and their contribution to symptoms of fatigue and exercise intolerance, is an increasingly important consideration as we develop rehabilitative strategies for improving motor performance and functional capacity in patients with HF.

The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6.

What is the central question of this study? Interleukin-6 has been associated with muscle mass and metabolism in both physiological and pathological conditions. A causal role for interleukin-6 in the induction of fatigue and disruption of mitochondrial function has not been determined. What is the main finding and its importance? We demonstrate that chronically elevated interleukin-6 increased skeletal muscle fatigability and disrupted mitochondrial content and function independent of changes in fibre type and mass. Interleukin-6 (IL-6) can initiate intracellular signalling in skeletal muscle by binding to the IL-6-receptor and interacting with the transmembrane gp130 protein. Circulating IL-6 has established effects on skeletal muscle mass and metabolism in both physiological and pathological conditions. However, the effects of circulating IL-6 on skeletal muscle function are not well understood. The purpose of this study was to determine whether chronically elevated systemic IL-6 was sufficient to disrupt skeletal muscle force, fatigue and mitochondrial function. Additionally, we examined the role of muscle gp130 signalling during overexpression of IL-6. Systemic IL-6 overexpression for 2weeks was achieved by electroporation of an IL-6 overexpression plasmid or empty vector into the quadriceps of either C57BL/6 (WT) or skeletal muscle gp130 knockout (KO) male mice. Tibialis anterior muscle in situ functional properties and mitochondrial respiration were determined. Interleukin-6 accelerated in situ skeletal muscle fatigue in the WT, with a 18.5% reduction in force within 90s of repeated submaximal contractions and a 7% reduction in maximal tetanic force after 5min. There was no difference between fatigue in the KO and KO+IL-6. Interleukin-6 reduced WT muscle mitochondrial respiratory control ratio by 36% and cytochromec oxidase activity by 42%. Interleukin-6 had no effect on either KO respiratory control ratio or cytochromec oxidase activity. Interleukin-6 also had no effect on body weight, muscle mass or tetanic force in either genotype. These results provide evidence that 2weeks of elevated systemic IL-6 is sufficient to increase skeletal muscle fatigability and decrease muscle mitochondrial content and function, and these effects require muscle gp130 signalling.

Understanding the burden of refractory myasthenia gravis.

Myasthenia gravis (MG) is an autoantibody-mediated disease that compromises the acetylcholine receptors or associated structures of the postsynaptic membrane of the neuromuscular junction. This leads to impaired neuromuscular transmission and subsequent fluctuating fatigability and weakness of ocular, bulbar, and limb skeletal muscles. Over the past few decades, there have been significant advances in our understanding of the disease pathophysiology and improvements in prognosis due to intensive care medicine and immunomodulation. Despite this, an estimated 10–20% of patients with MG do not achieve an adequate response, are intolerant to conventional treatment, or require chronic treatment with intravenous immunoglobulins or plasma separation procedures. Such patients are regarded as having MG that is ‘refractory’ to treatment and may represent a distinct clinical subgroup. Because the majority of patients with MG have well-controlled disease, the burden of illness in the minority with refractory disease is poorly understood and may be underestimated. However, clinically these patients are liable to experience extreme fatigue, considerable disability owing to uncontrolled symptoms, and frequent myasthenic crises and hospitalizations. Both acute adverse effects and an increased risk of comorbidity from treatment regimens may contribute to reduced quality of life. As yet, little is known concerning the impact of refractory MG on mental health and health-related quality of life. This review aims to highlight the burden of disease and unmet needs in patients with refractory MG.