Sex differences in the involvement of skeletal and cardiac muscles in myopathic Ano5-/- mice.

Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by recessive mutations in the Anoctamin-5 gene (ANO5, TMEM16E). Although ANO5 myopathy is not X-chromosome linked, we performed a meta-analysis of the research literature and found that three-quarters of LGMD-R12 patients are males. Females are less likely to present with moderate to severe skeletal muscle and/or cardiac pathology. Because these sex differences could be explained in several ways, we compared males and females in a mouse model of LGMD-R12. This model recapitulates the sex differences in human LGMD-R12. Only male Ano5-/- mice had elevated serum creatine kinase after exercise and exhibited defective membrane repair after laser injury. In contrast, by these measures, female Ano5-/- mice were indistinguishable from wild type. Despite these differences, both male and female Ano5-/- mice exhibited exercise intolerance. While exercise intolerance of male mice can be explained by skeletal muscle dysfunction, echocardiography revealed that Ano5-/- female mice had features of cardiomyopathy that may be responsible for their exercise intolerance. These findings heighten concerns that mutations of ANO5 in humans may be linked to cardiac disease.

Whole Exome Sequencing detects PYGM variants in two adults with McArdle disease

McArdle disease is a progressive and debilitating glycogen storage disease with typical onset in late childhood. Here we describe a former competitive athlete with early adult onset McArdle disease and a septuagenarian with a history of exercise-intolerance since adolescence who was evaluated for proximal muscle weakness. Exome sequencing identified bi-allelic variants in PYGM gene for both cases. The former athlete has the common, well-known pathogenic variant p.(Arg50Ter) in trans with a novel missense variant, p.(Asp694Glu). The second individual has a previously described homozygous missense variant, p.(Arg771Gln). Here, we describe the clinical course, enzyme-testing results using muscle tissue and molecular findings for the individuals, and add to the knowledge of the genotypic spectrum of this disorder.

Benefits of Home-Based Exercise Training Following Critical SARS-CoV-2 Infection: A Case Report

In the current scenario, in which an elevated number of COVID-19 survivors present with severe physical deconditioning, exercise intolerance, persistent symptoms, and other post-acute consequences, effective rehabilitation strategies are of utmost relevance. In this study, we report for the first time the effect of home-based exercise training (HBET) in a survivor patient from critical COVID-19 illness. A 67-year-old woman who had critical COVID-19 disease [71 days of hospitalization, of which 49 days were in the intensive care unit (ICU) with invasive mechanical ventilation due to respiratory failure] underwent a 10-week HBET aiming to recovering overall physical condition. Before and after the intervention, we assessed cardiopulmonary parameters, skeletal muscle strength and functionality, fatigue severity, and self-reported persistent symptoms. At baseline (3 months after discharge), she presented with severe impairment in cardiorespiratory functional capacity (<50% age predicted VO2peak). After the intervention, remarkable improvements in VO2peak (from 10.61 to 15.48 mL·kg−1·min−1, Δ: 45.9%), oxygen uptake efficiency slope (OUES; from 1.0 to 1.3 L·min−1, Δ: 30.1%), HR/VO2 slope (from 92 to 52 bpm·L−1, Δ: −43.5%), the lowest VE/VCO2 ratio (from 35.4 to 32.9 L·min−1, Δ: −7.1%), and exertional dyspnea were observed. In addition, handgrip strength (from 22 to 27 kg, Δ: 22.7%), 30-s Sit-to-Stand (30-STS; from 14 to 16 repetitions, Δ:14.3%), Timed-Up-and-Go (TUG; from 8.25 to 7.01 s, Δ: −15%) performance and post-COVID functional status (PCFS) score (from 4 to 2) were also improved from baseline to post-intervention. Self-reported persistent symptoms were also improved, and Fatigue Severity Scale (FSS) score decreased (from 4 to 2.7) from baseline to post-intervention. This is the first evidence that a semi-supervised, HBET program may be safe and potentially effective in improving cardiorespiratory and physical functionality in COVID-19 survivors. Controlled studies are warranted to confirm these findings.

Muscle-Skeletal Abnormalities and Muscle Oxygenation during Isokinetic Strength Exercise in Heart Failure with Preserved Ejection Fraction Phenotype: A Cross-Sectional Study

Exercise intolerance, a hallmark of patients with heart failure (HF), is associated with muscle weakness. However, its causative microcirculatory and muscle characteristics among those with preserved or reduced ejection fraction (HFpEF or HFrEF) phenotype is unclear. The musculoskeletal abnormalities that could result in impaired peripheral microcirculation are sarcopenia and muscle strength reduction in HF, implying lowered oxidative capacity and perfusion affect transport and oxygen utilization during exercise, an essential task from the microvascular muscle function. Besides that, skeletal muscle microcirculatory abnormalities have also been associated with exercise intolerance in HF patients who also present skeletal muscle myopathy. This cross-sectional study aimed to compare the muscle microcirculation dynamics via near-infrared spectroscopy (NIRS) response during an isokinetic muscle strength test and ultrasound-derived parameters (echo intensity was rectus femoris muscle, while the muscle thickness parameter was measured on rectus femoris and quadriceps femoris) in heart failure patients with HFpEF and HFrEF phenotypes and different functional severities (Weber Class A, B, and C). Twenty-eight aged-matched patients with HFpEF (n = 16) and HFrEF (n = 12) were assessed. We found phenotype differences among those with Weber C severity, with HFrEF patients reaching lower oxyhemoglobin (O2Hb, μM) (−10.9 ± 3.8 vs. −23.7 ± 5.7, p = 0.029) during exercise, while HFpEF reached lower O2Hb during the recovery period (−3.0 ± 3.4 vs. 5.9 ± 2.8, p = 0.007). HFpEF with Weber Class C also presented a higher echo intensity than HFrEF patients (29.7 ± 8.4 vs. 15.1 ± 6.8, p = 0.017) among the ultrasound-derived variables. Our preliminary study revealed more pronounced impairments in local microcirculatory dynamics in HFpEF vs. HFrEF patients during a muscle strength exercise, combined with muscle-skeletal abnormalities detected via ultrasound imaging, which may help explain the commonly observed exercise intolerance in HFpEF patients.

The H2FPEF and HFA-PEFF algorithms for predicting exercise intolerance and abnormal hemodynamics in heart failure with preserved ejection fraction

Exercise intolerance is a primary manifestation in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with abnormal hemodynamics and a poor quality of life. Two multiparametric scoring systems have been proposed to diagnose HFpEF. This study sought to determine the performance of the H2FPEF and HFA-PEFF scores for predicting exercise capacity and echocardiographic findings of intracardiac pressures during exercise in subjects with dyspnea on exertion referred for bicycle stress echocardiography. In a subset, simultaneous expired gas analysis was performed to measure the peak oxygen consumption (VO2). Patients with HFpEF (n = 83) and controls without HF (n = 104) were enrolled. The H2FPEF score was obtainable for all patients while the HFA-PEFF score could not be calculated for 23 patients (feasibility 88%). Both H2FPEF and HFA-PEFF scores correlated with a higher E/e′ ratio (r = 0.49 and r = 0.46), lower systolic tricuspid annular velocity (r = − 0.44 and = − 0.24), and lower cardiac output (r = − 0.28 and r = − 0.24) during peak exercise. Peak VO2 and exercise duration decreased with an increase in H2FPEF scores (r = − 0.40 and r = − 0.32). The H2FPEF score predicted a reduced aerobic capacity (AUC 0.71, p = 0.0005), but the HFA-PEFF score did not (p = 0.07). These data provide insights into the role of the H2FPEF and HFA-PEFF scores for predicting exercise intolerance and abnormal hemodynamics in patients presenting with exertional dyspnea.

Stimulating the sir2-pgc-1α axis rescues exercise capacity and mitochondrial respiration in Drosophila tafazzin mutants.

Cardiolipin (CL) is a phospholipid required for proper mitochondrial function. Tafazzin remodels CL to create highly unsaturated fatty acid chains. However, when tafazzin is mutated, CL remodeling is impeded, leading to mitochondrial dysfunction and the disease Barth syndrome. Patients with Barth syndrome often have severe exercise intolerance, which negatively impacts their overall quality of life. Boosting NAD+ levels can improve symptoms of other mitochondrial diseases, but its effect in the context of Barth syndrome has not been examined. We demonstrate for the first time that nicotinamide riboside (NR) can rescue exercise tolerance and mitochondrial respiration in a Drosophila tafazzin mutant and that the beneficial effects are dependent on sir2 and pgc-1α . Overexpressing pgc-1α increased the total abundance of cardiolipin in mutants. In addition, muscles and neurons were identified as key targets for future therapies because sir2 or pgc-1α overexpression in either of these tissues is sufficient to restore the exercise capacity of Drosophila tafazzin mutants.

Exercise Intolerance, Benefits, and Prescription for People Living With a Fontan Circulation: The Fontan Fitness Intervention Trial (F-FIT)—Rationale and Design

Background: Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe—and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials.Aims and Methods: The Fontan Fitness Intervention Trial (F-FIT)—a phase III clinical trial—aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (<16 years) will be randomized to either a physical activity and exercise program of moderate-to-vigorous intensity or usual care in a two-arm trial with a 1:1 allocation. The primary outcome is a change in aerobic exercise capacity (peak oxygen uptake) at 4-months. Secondary outcomes include safety, and changes in cardiopulmonary exercise testing measures, peripheral venous pressure, respiratory muscle and lung function, body composition, liver stiffness, neuropsychological and neurocognitive function, physical activity levels, dietary and nutritional status, vascular function, neurohormonal activation, metabolites, cardiac function, quality of life, musculoskeletal fitness, and health care utilization. Outcome measures will be assessed at baseline, 4-months, and 12-months. This manuscript will describe the pathophysiology of exercise intolerance in the Fontan circulation and the rationale and protocol for the F-FIT.

A Novel Coq8a Mutation in a Case with Juvenile Onset Coq10d4: Case Report and Literature Review

Primary coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Molecular pathology responsible for clinical findings is mitochondrial respiratory chain dysfunction. The main clinical manifestation involves early onset exercise intolerance, progressive cerebellar ataxia and movement disorders. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. COQ8A gene mutations are responsible for this disease. Here we present a patient with tremor and cerebellar atrophy in which we detected a new mutation in the COQ8A gene. The patient's clinical findings were compatible with juvenile onset COQ10D4. Therefore, we reviewed the clinical, laboratory and genetic findings of 11 juvenile-onset COQ10D4 patients reported to date, as well as the patient's presentation.

Late Exercise Tolerance Testing Using a Dynamic High Intensity Interval Multidirectional Movement Protocol

ObjectiveAnalyze the utility of a 5-step exertional rehab protocol (ERP) that included High Intensity Interval Multi-Directional Movement (HIIT-MD) or step 5. We assessed the incidence and etiologies of exercise intolerance (EI) during Step 5 in concussed patients who tolerated maximal linear exertion.BackgroundExertional testing can be used to determine appropriate levels of exercise tolerance (ET) in concussed patients. Traditionally linear modalities have been used to determine max ET prior to clearance. HIIT-MD protocols can be the next appropriate step to bridge clearance for more dynamic activities.Design/MethodsRetrospective chart review included 130 step 5 trials for EI; of those, 72 had pre/postexercise King Devick (KD) and force plate (FP) testing. Patients were 10–59 years old and clinic visits occurred 2019–2020. EI rate was recorded and failure reason was documented by our clinic's concussion specialist. The difference between pre/post exercise KD and FP was investigated.ResultsOf 130 step 5 trials, 21.54% failed due to EI. Reason for EI included the onset of symptoms (82.1%), followed by signs of dysautonomia (39.3%). Symptoms and dysautonomia combined were noted in 35.7% of those with EI. Symptoms appeared in combination with another marker 69.6% of the time. The average change in KD times pre/post exercise testing was +2.52 seconds longer in the EI group compared to −2.45 seconds shorter in the ET group (p = 0.62). The EI group demonstrated an average change of 0.36 deg/sec sway velocity increase after exercise compared to 0.13 deg/sec in the ET group (p = 0.93).ConclusionsThere is evidence for the utility of a HITT-MD protocol for dynamic exercise/sports clearance. Exercise testing progression and concussion clearance should include a dynamic HITT-MD protocol to ascertain no late phase dynamic EI. Dysautonomia and/or vestibulocular aggravation may be contributors to late phase EI. If EI exists, identifying and targeting underlying causes can aid optimal recovery.