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Bruce H. Cohen - One of the best experts on this subject based on the ideXlab platform.
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A novel exercise testing algorithm to diagnose Mitochondrial Myopathy.
Muscle & nerve, 2021Co-Authors: Rajeev Bhatia, Bruce H. Cohen, Neil L. McninchAbstract:INTRODUCTION Oxygen uptake efficiency slope (OUES) is a noninvasive cardiopulmonary exercise testing (CPET) measurement based on oxygen uptake (V˙O2 ) and minute ventilation (V˙E) and is a marker of the efficiency of oxygen utilization by the body. However, it has not been studied in Mitochondrial disorders. We explored noninvasive CPET parameters, including OUES, as a way to reliably diagnose Mitochondrial Myopathy. METHODS We performed cycle ergometer maximal exercise testing on definite and suspected Mitochondrial Myopathy subjects (MM-D and MM-S) and their age- and sex-matched controls. OUES was corrected for body surface area (OUES/BSA) to eliminate the effect of body size. RESULTS A total of 40 participants, including 20 MM-D (n = 13; 6 males; aged 14-64 years) and 7 MM-S (5 males, aged 11-30 years) subjects and 20 controls, completed the study. MM-D subjects showed lower aerobic fitness than controls. OUES/BSA was lower in MM-D subjects, suggesting inefficient oxygen utilization. Area under the curve (AUC) and 95% confidence interval (CI) for OUES/BSA (AUC, 0.91; 95% CI, 0.80-1.00), peak V˙O2 percent predicted (AUC, 0.95; 95% CI, 0.86-1.00), and V˙O2 /work slope (AUC, 0.94; 95% CI, 0.85-1.00) showed excellent ability to diagnose Mitochondrial Myopathy in MM-D subjects. We applied a diagnostic approach based on the parameters just noted to MM-S subjects and their controls and were able to support or disprove the diagnosis of Mitochondrial Myopathy. DISCUSSION We proposed and applied an approach based on the aformentioned three CPET parameters to diagnose Mitochondrial Myopathy reliably and found it to be clinically useful.
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a randomized crossover trial of elamipretide in adults with primary Mitochondrial Myopathy
Journal of Cachexia Sarcopenia and Muscle, 2020Co-Authors: Amel Karaa, Jerry Vockley, Richard H Haas, Amy Goldstein, Bruce H. CohenAbstract:BACKGROUND: This study aims to evaluate the effect of subcutaneous (SC) elamipretide dosing on exercise performance using the 6 min walk test (6MWT), patient-reported outcomes measuring fatigue, functional assessments, and safety to guide the development of the Phase 3 trial. METHODS: MMPOWER-2 was a randomized, double-blind, placebo-controlled, crossover trial that enrolled participants (N = 30) with genetically confirmed primary Mitochondrial Myopathy. Participants were randomly assigned (1:1) to 40 mg/day SC elamipretide for 4 weeks followed by placebo SC for 4 weeks, separated by a 4-week washout period, or the opposite sequence. The primary endpoint was the distance walked on the 6MWT. RESULTS: The distance walked on the 6MWT by the elamipretide-treated participants was 398.3 (+/-134.16) meters compared with 378.5 (+/-125.10) meters in the placebo-treated group, a difference of 19.8 m (95% confidence interval, -2.8, 42.5; P = 0.0833). The results of the Primary Mitochondrial Myopathy Symptom Assessment Total Fatigue and Total Fatigue During Activities scores showed that participants treated with elamipretide reported less fatigue and muscle complaints compared with placebo (P = 0.0006 and P = 0.0018, respectively). Additionally, the Neuro-QoL Fatigue Short Form and Patient Global Assessment showed reductions in symptoms (P = 0.0115 and P = 0.0421, respectively). In this 4-week treatment period, no statistically significant change was observed in the Physician Global Assessment (P = 0.0636), the Triple Timed Up and Go (P = 0.8423) test, and wrist/hip accelerometry (P = 0.9345 and P = 0.7326, respectively). Injection site reactions were the most commonly reported adverse events with elamipretide (80%), the majority of which were mild. No serious adverse events or deaths were reported. CONCLUSIONS: Participants who received a short-course treatment of daily SC elamipretide for 4 weeks experienced a clinically meaningful change in the 6MWT, which did not achieve statistical significance as the primary endpoint of the study. Secondary endpoints were suggestive of an elamipretide treatment effect compared with placebo. Nominal statistically significant and clinically meaningful improvements were seen in patient-reported outcomes. The results of this trial provided an efficacy signal and data to support the initiation of MMPOWER-3, a 6-month long, Phase 3 treatment trial in patients with primary Mitochondrial Myopathy.
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safety and efficacy of omaveloxolone in patients with Mitochondrial Myopathy motor trial
Neurology, 2020Co-Authors: Karen Lindhardt Madsen, Amel Karaa, Bruce H. Cohen, Amy Goldstein, Astrid Emilie Buch, Marni J Falk, Angela Goldsberry, Mary Kay Koenig, Colleen C Muraresku, Colin MeyerAbstract:Objective To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with Mitochondrial Myopathy. Methods In cohorts of 8–13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory). Results No differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent. Conclusions Omaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved Mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with Mitochondrial Myopathy, which encourages further investigations of omaveloxolone in this patient group. Clinicaltrials.gov identifier NCT02255422. Classification of evidence This study provides Class II evidence that, for patients with Mitochondrial Myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.
Ronald G Haller - One of the best experts on this subject based on the ideXlab platform.
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metabolic profiles of exercise in patients with mcardle disease or Mitochondrial Myopathy
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Ronald G Haller, Nigel F Delaney, Rohit Sharma, Laura Tadvalkar, Clary B Clish, Vamsi K MoothaAbstract:McArdle disease and Mitochondrial Myopathy impair muscle oxidative phosphorylation (OXPHOS) by distinct mechanisms: the former by restricting oxidative substrate availability caused by blocked glycogen breakdown, the latter because of intrinsic respiratory chain defects. We applied metabolic profiling to systematically interrogate these disorders at rest, when muscle symptoms are typically minimal, and with exercise, when symptoms of premature fatigue and potential muscle injury are unmasked. At rest, patients with Mitochondrial disease exhibit elevated lactate and reduced uridine; in McArdle disease purine nucleotide metabolites, including xanthine, hypoxanthine, and inosine are elevated. During exercise, glycolytic intermediates, TCA cycle intermediates, and pantothenate expand dramatically in both Mitochondrial disease and control subjects. In contrast, in McArdle disease, these metabolites remain unchanged from rest; but urea cycle intermediates are increased, likely attributable to increased ammonia production as a result of exaggerated purine degradation. Our results establish skeletal muscle glycogen as the source of TCA cycle expansion that normally accompanies exercise and imply that impaired TCA cycle flux is a central mechanism of restricted oxidative capacity in this disorder. Finally, we report that resting levels of long-chain triacylglycerols in Mitochondrial Myopathy correlate with the severity of OXPHOS dysfunction, as indicated by the level of impaired O2 extraction from arterial blood during peak exercise. Our integrated analysis of exercise and metabolism provides unique insights into the biochemical basis of these muscle oxidative defects, with potential implications for their clinical management.
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venous oxygen levels during aerobic forearm exercise an index of impaired oxidative metabolism in Mitochondrial Myopathy
Annals of Neurology, 2002Co-Authors: Tanja Taivassalo, Ronald G Haller, Amy Abbott, Phil WyrickAbstract:A cardinal feature of impaired skeletal muscle oxidative metabolism in Mitochondrial myopathies is a limited ability to increase the extraction of O(2) from blood relative to the increase in O(2) delivery by the circulation during exercise. We investigated whether aerobic forearm exercise would result in an abnormal increase in venous effluent O(2) in patients with impaired skeletal muscle oxidative phosphorylation attributable to Mitochondrial disease. We monitored the partial pressure of O(2) (PO(2)) in cubital venous blood at rest, during handgrip exercise, and during recovery in 13 patients with Mitochondrial Myopathy and exercise intolerance and in 13 healthy control and 11 patient control subjects. Resting and recovery venous effluent PO(2) were similar in all subjects, but during exercise venous PO(2) paradoxically rose in Mitochondrial Myopathy patients from 27.2 +/- 4.0mmHg to 38.2 +/- 13.3mmHg, whereas PO(2) fell from 27.2 +/- 4.2mmHg to 24.2 +/- 2.7mmHg in healthy subjects and from 27.4 +/- 9.5mmHg to 22.2 +/- 5.2mmHg in patient controls. The range of elevated venous PO(2) during forearm exercise in Mitochondrial Myopathy patients (32 to 82mmHg) correlated closely with the severity of oxidative impairment as assessed during cycle exercise. We conclude that measurement of venous PO(2) during aerobic forearm exercise provides an easily performed screening test that sensitively detects impaired O(2) use and accurately assesses the severity of oxidative impairment in patients with Mitochondrial Myopathy and exercise intolerance.
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exercise fuel mobilization in Mitochondrial Myopathy a metabolic dilemma
Annals of Neurology, 1996Co-Authors: John Vissing, Henrik Galbo, Ronald G HallerAbstract:In Mitochondrial Myopathy, severely impaired muscle oxidative capacity poses a dilemma for metabolic regulation in exercise. We inquired whether fuel mobilization during exercise in Mitochondrial Myopathy is adjusted to the reduced capacity to oxidize substrate, or if fuel is mobilized in excess of oxidative capacity. Hormonal and metabolic responses to 20 minutes of cycle exercise were studied in 4 patients with Mitochondrial Myopathy working at near maximal effort and in 4 healthy matched controls. On 2 separate days, controls were studied at the same absolute (A) workload (9 +/- 3 W) and the same relative (R) workload (77 +/- 9 W) as performed by the patients. During exercise, average glucose production was higher in patients (28 +/- 5 micromol min(-1) kg(-1)) than in controls at both workloads (A, 12 +/- 1; R, 18 +/- 2 micromol min(-1) kg(-1)). Exercise-induced increases in plasma glucose, growth hormone, epinephrine, norepinephrine, corticotropin, and lactate, and decreases in plasma insulin and pH were also larger in patients compared with findings in controls at both workloads. In conclusion, Mitochondrial myopathies are associated with excessive neuroendocrine responses and mobilization of glucose during exercise. These responses augment ATP synthesis but result in progressive accumulation of nonoxidized substrates. Apparently, substrate mobilization and neuroendocrine responses in exercise are linked to oxidative demand rather than to oxidative capacity in working muscle.
Anu Suomalainen - One of the best experts on this subject based on the ideXlab platform.
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Effect of bezafibrate treatment on late-onset Mitochondrial Myopathy in mice
Human Molecular Genetics, 2011Co-Authors: Shuichi Yatsuga, Anu SuomalainenAbstract:Mitochondrial dysfunction is an important cause of metabolic disorders of children and adults, with no effective therapy options. Recently, induction of Mitochondrial biogenesis, by transgenic overexpression of PGC1-alpha [peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1-alpha], was reported to delay progression of early-onset cytochrome-c-oxidase (COX) deficiency in skeletal muscle of two mouse models: a muscle-specific knock-out of COX10 (COX10-mKO) and a constitutive knock-out of Surf1 (Surf1-KO). A pan-PPAR agonist, bezafibrate, could similarly delay Myopathy progression in COX10-mKOs, but not in SURF1-KOs. We asked whether bezafibrate affected disease progression in late-onset adult-type Mitochondrial Myopathy mice. These 'Deletor mice' express a dominant patient mutation in Twinkle-helicase, leading to accumulation of multiple mtDNA deletions and subsequent progressive respiratory chain (RC) deficiency with COX-negative muscle fibers at 12 months of age. The primary and secondary molecular findings in Deletor mice mimic closely those in patients with Twinkle Myopathy. We applied 0.5% bezafibrate diet to Deletors for 22 weeks, starting at disease manifestation, mimicking patient treatment after diagnosis. Bezafibrate delayed significantly the accumulation of COX-negative fibers and multiple mtDNA deletions. However, Mitochondrial biogenesis was not induced: Mitochondrial DNA copy number, transcript and RC protein amounts decreased in both Deletors and wild-type mice. Furthermore, bezafibrate induced severe lipid oxidation effects, with hepatomegaly and loss of adipose tissue, the mechanism involving lipid mobilization by high hepatic expression of FGF21 cytokine. However, as bezafibrate has been tolerated well by humans, the beneficial muscle findings in Deletor mice support consideration of bezafibrate trials on adult patients with Mitochondrial Myopathy.
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ketogenic diet slows down Mitochondrial Myopathy progression in mice
Human Molecular Genetics, 2010Co-Authors: Sofia Tuulikki Aholaerkkila, Anu Suomalainen, Christopher Carroll, Katja Peltolamjosund, Valtteri Tulkki, Ismo Mattila, Tuulikki Seppanenlaakso, Matej Oresic, Henna TyynismaaAbstract:Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant Mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset Mitochondrial Myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in Mitochondrial RC deficiencies, and prevented completely the formation of the Mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced Mitochondrial biogenesis and restored liver lipid levels. Our results show that Mitochondrial Myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for Mitochondrial late-onset myopathies.
Nathan Fischel-ghodsian - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Myopathy and sideroblastic anemia.
American journal of medical genetics. Part A, 2004Co-Authors: Kari A Casas, Nathan Fischel-ghodsianAbstract:We report four new cases of Mitochondrial Myopathy and sideroblastic anemia (MSA). Hallmark features of MSA include progressive exercise intolerance during childhood, onset of sideroblastic anemia around adolescence, basal lactic acidemia, and Mitochondrial Myopathy. Autosomal recessive inheritance of MSA in the family we describe is assumed due to the presence of two affected sibling pairs, unaffected parents, an unaffected sibling, and parental consanguinity. The nuclear families we describe are paternally related and originate from the same Iranian city as a family with MSA described by [Inbal et al., 1995]. These families provide an opportunity to clarify the molecular basis of tissue specific expression of Mitochondrial disorders.
John Vissing - One of the best experts on this subject based on the ideXlab platform.
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Hydroxylated Long-Chain Acylcarnitines are Biomarkers of Mitochondrial Myopathy
The Journal of clinical endocrinology and metabolism, 2019Co-Authors: Christoffer Rasmus Vissing, Morten Duno, Flemming Wibrand, Mette Christensen, John VissingAbstract:CONTEXT Plasma acylcarnitines are biomarkers of β-oxidation and are useful in diagnosing several inborn errors of metabolism but have never been investigated systematically in patients with Mitochondrial Myopathy. OBJECTIVE We hypothesized that acylcarnitines can also be biomarkers of Mitochondrial Myopathy and sought to investigate the prevalence and pattern of elevated acylcarnitines. DESIGN This was a prospective cohort study of patients with confirmed Mitochondrial Myopathy followed at Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark. PATIENTS We included 35 patients (44 ± 15 years, 15 women) with Mitochondrial Myopathy caused by single, large-scale deletions of Mitochondrial DNA (n = 17), pathogenic variants in Mitochondrial transfer RNA (n = 13), or in proteins of the respiratory chain complexes (n = 5).Concentrations of 35 acylcarnitines were measured using ultra-HPLC and tandem mass-spectrometry. Findings were compared with muscle mutation load in all patients and to respiratory chain activity in 26 patients. MAIN OUTCOME MEASURES Prevalence of elevated concentrations of acylcarnitines related to acyl-coenzyme A (CoA) dehydrogenases in patients with Mitochondrial Myopathy and relation to genotypes/phenotypes. RESULTS In total, 27 (77%) patients had elevated concentrations of acylcarnitines related to acyl-CoA dehydrogenases. Elevated concentrations of seven acylcarnitine species were more common in patients compared with a control cohort of >900 individuals, and a specific pattern involving hydroxylated long-chain acylcarnitines occurred in 22 (63%) patients. Severity of derangements was correlated with muscle mutation load and genotypes/phenotypes. CONCLUSION In conclusion, elevated concentrations of acylcarnitines is common in patients with Mitochondrial Myopathy and shows a specific pattern affecting hydroxylated long-chain acylcarnitines, which can have implications for future diagnostic workup of patients.
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Growth and differentiation factor 15 as a biomarker for Mitochondrial Myopathy.
Mitochondrion, 2019Co-Authors: N. Poulsen, Karen Lindhardt Madsen, Tessa Munkeboe Hornsyld, Anne-sofie Vibæk Eisum, Freja Fornander, Astrid Emilie Buch, Mads G. Stemmerik, Cristina Ruiz-ruiz, Thomas O. Krag, John VissingAbstract:Abstract Objective We investigated if Growth and Differentiation Factor 15 (GDF-15) can be used as a biomarker to distinguish patients with Mitochondrial Myopathy from patients with other myopathies. Methods Serum GDF-15 was measured in 28 patients with Mitochondrial disease, 24 with metabolic myopathies, 27 with muscular dystrophy and 21 healthy controls. Results and conclusions Our findings indicate that elevated GDF-15 can distinguish patients with Mitochondrial Myopathy from other myopathies, including metabolic myopathies. This suggests that increases in GDF-15 is specific to respiratory chain dysfunction rather than general metabolic dysfunction or muscle defect.
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A forearm exercise screening test for Mitochondrial Myopathy.
Neurology, 2002Co-Authors: Tina Dysgaard Jensen, Pedram Kazemi-esfarjani, Elwira Skomorowska, John VissingAbstract:Background: The authors hypothesized that impaired oxygen extraction in Mitochondrial Myopathy (MM) results in a high oxygen saturation in venous effluent blood from working muscle and that this phenomenon can be used as a diagnostic tool for MM. Methods: Twelve patients with MM, 10 patients with muscular dystrophy, and 12 healthy subjects were studied. All subjects performed intermittent static handgrip exercise (1/2 Hz) at 40% of maximal voluntary contraction (MVC) for 3 minutes. Cubital venous oxygen saturation and brachial artery flow were measured in the exercised arm. Results: Exercise-induced venous oxygen desaturation was smaller in patients with MM (Δ − 7 ± 5%) than in subjects with muscular dystrophy (Δ − 38 ± 2%; p = 0.00001) and healthy subjects (Δ − 43 ± 2%; p = 0.0000002). MVC and exercise blood flow were similar in patients with MM (18 ± 3 kg; 436 ± 65 mL/min) and patients with muscular dystrophy (15 ± 3 kg; 460 ± 85 mL/min), but were higher in healthy subjects (32 ± 4 kg; 630 ± 58 mL/min; p p = 0.007). Conclusion: Oxygen desaturation in venous blood from exercising muscle is markedly lower in patients with Mitochondrial Myopathy than in subjects with other muscle diseases and healthy subjects, suggesting that a forearm exercise test can be a diagnostic screening tool for Mitochondrial Myopathy.
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exercise fuel mobilization in Mitochondrial Myopathy a metabolic dilemma
Annals of Neurology, 1996Co-Authors: John Vissing, Henrik Galbo, Ronald G HallerAbstract:In Mitochondrial Myopathy, severely impaired muscle oxidative capacity poses a dilemma for metabolic regulation in exercise. We inquired whether fuel mobilization during exercise in Mitochondrial Myopathy is adjusted to the reduced capacity to oxidize substrate, or if fuel is mobilized in excess of oxidative capacity. Hormonal and metabolic responses to 20 minutes of cycle exercise were studied in 4 patients with Mitochondrial Myopathy working at near maximal effort and in 4 healthy matched controls. On 2 separate days, controls were studied at the same absolute (A) workload (9 +/- 3 W) and the same relative (R) workload (77 +/- 9 W) as performed by the patients. During exercise, average glucose production was higher in patients (28 +/- 5 micromol min(-1) kg(-1)) than in controls at both workloads (A, 12 +/- 1; R, 18 +/- 2 micromol min(-1) kg(-1)). Exercise-induced increases in plasma glucose, growth hormone, epinephrine, norepinephrine, corticotropin, and lactate, and decreases in plasma insulin and pH were also larger in patients compared with findings in controls at both workloads. In conclusion, Mitochondrial myopathies are associated with excessive neuroendocrine responses and mobilization of glucose during exercise. These responses augment ATP synthesis but result in progressive accumulation of nonoxidized substrates. Apparently, substrate mobilization and neuroendocrine responses in exercise are linked to oxidative demand rather than to oxidative capacity in working muscle.