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L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome.

ABSTRACT: OBJECTIVE:To study the effects of L-arginine (L-Arg) on total body aerobic capacity and muscle metabolism as assessed by (31)Phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS) in patients with MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) syndrome. METHODS:We performed a case control study in 3 MELAS siblings (m.3243A>G tRNA(leu(UUR)) in MTTL1 gene) with different % blood mutant mtDNA to evaluate total body maximal aerobic capacity (VO(2peak)) using graded cycle ergometry and muscle metabolism using 31P-MRS. We then ran a clinical trial pilot study in MELAS sibs to assess response of these parameters to single dose and a 6-week steady-state trial of oral L-Arginine. RESULTS:At baseline (no L-Arg), MELAS had lower serum Arg (p = 0.001). On 3(1)P-MRS muscle at rest, MELAS subjects had increased phosphocreatine (PCr) (p = 0.05), decreased ATP (p = 0.018), and decreased intracellular Mg(2+) (p = 0.0002) when compared to matched controls. With L-arginine therapy, the following trends were noted in MELAS siblings on cycle ergometry: (1) increase in mean % maximum work at anaerobic threshold (AT) (2) increase in % maximum heart rate at AT (3) small increase in VO(2peak). On (31)P-MRS the following mean trends were noted: (1) A blunted decrease in pH after exercise (less acidosis) (2) increase in Pi/PCr ratio (ADP) suggesting increased work capacity (3) a faster half time of PCr recovery (marker of mitochondrial activity) following 5 minutes of moderate intensity exercise (4) increase in torque. SIGNIFICANCE:These results suggest an improvement in aerobic capacity and muscle metabolism in MELAS subjects in response to supplementation with L-Arg. Intramyocellular hypomagnesemia is a novel finding that warrants further study. CLASSIFICATION OF EVIDENCE:Class III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects. TRIAL REGISTRATION:ClinicalTrials.gov NCT01603446.

SUBMITTER: Rodan LH

PROVIDER: S-EPMC4439047 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:We previously showed that MELAS patients have decreased cerebrovascular reactivity (CVR) (p? 0.002) and increased cerebral blood flow (CBF) (p<0.0026); changes correlated with disease severity and % mutant mtDNA (inversely for CVR; directly for CBF). We ran a prospective pilot in 3 MELAS sibs (m.3243A>G tRNALeu(UUR)) with variable % mutant blood mtDNA to assess effects of L-Arginine (L-Arg) (single dose and 6-wk steady-state trial) on regional CBF, arterial CVR and neurovascular coupling. METHODS:Patients were studied with 3T MRI using arterial spin labeling (ASL) to measure CBF and changes in % Blood Oxygen Level Dependent (BOLD) signal to changes in arterial partial pressure of CO2 to measure CVR. Task fMRI consisted of an alternating black and white checkerboard to evaluate visual cortex response in MELAS and controls. RESULTS:Following L-Arg, there was restoration of serum Arg (76-230 ?M) in MELAS sibs and a trend towards increasing CVR in frontal and corresponding decrease in occipital cortex; CVR was unchanged globally. There was a 29-37% reduction in baseline CBF in one patient following 6 wks of L-Arg. Pre-treatment fMRI activation in response to visual cortex stimulus was markedly decreased in the same patient compared to controls in primary visual striate cortex V1 and extrastriate regions V2 to V5 with a marked increase toward control values following a single dose and 6 wks of L-Arg. CONCLUSION:Proposed "healing" effect may be due to more efficient utilization of energy substrates with increased cellular energy balances and ensuing reduction in signalling pathways that augment flow in the untreated state. CLASSIFICATION OF EVIDENCE:This prospective pilot study provides Class III evidence that oral L-Arginine (100 mg/kg single dose or 100 mg/kg three times daily po X 6 weeks) normalizes resting blood flow from elevated pre-treatment levels in patients with MELAS syndrome, selectively increases their CVR from reduced pre-treatment levels in regions most impaired at the expense of less abnormal regions, and normalizes reduced BOLD fMRI activation in response to visual cortex stimulus. CLINICAL TRIALS.GOV (NIH):NCT01603446.

Project description:Background and objectivesStroke management in the context of primary mitochondrial disease is clinically challenging, and the best treatment options for patients with stroke-like episodes remain uncertain. We sought to perform a systematic review of the safety and efficacy of l-arginine use in the acute and prophylactic management of stroke-like episodes in patients with mitochondrial disease.MethodsThe systematic review was registered in PROSPERO (CRD42020181230). We searched 6 databases from inception to January 15, 2021: MEDLINE, Embase, Scopus, Web of Science, CINAHL, and ClinicalTrials.gov. Original articles and registered trials available, in English, reporting l-arginine use in the acute or prophylactic management of stroke-like episodes in patients with genetically confirmed mitochondrial disease were eligible for inclusion. Data on safety and treatment response were extracted and summarized by multiple observers. Risk of bias was assessed by the methodologic quality of case reports, case series, and a risk-of-bias checklist for nonrandomized studies. Quality of evidence was synthesized with the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grade of Recommendations. The predetermined main outcome measures were clinical response to l-arginine treatment, adverse events, withdrawals, and deaths (on treatment and/or during follow-up), as defined by the author.ResultsThirty-seven articles met inclusion criteria (0 randomized controlled trials; 3 open-label; 1 retrospective cohort; 33 case reports/case series) (N = 91 patients; 86% m.3243A>G). In the case reports, 54% of patients reported a positive clinical response to acute l-arginine, of which 40% were concomitantly treated with antiepileptic drugs. Improved headache at 24 hours was the greatest reported benefit in response to IV l-arginine in the open-label trials (31 of 39, 79%). In 15 of 48 patients (31%) who positively responded to prophylactic l-arginine, antiepileptic drugs were either used (7 of 15) or unreported (8 of 15). Moderate adverse events were reported in the follow-up of both IV and oral l-arginine treatment, and 11 patients (12%) died during follow-up or while on prophylactic treatment.DiscussionThe available evidence is of poor methodologic quality and classified as Level 5. IV and oral l-arginine confers no demonstrable clinical benefit in either the acute or prophylactic treatment of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, with more robust controlled trials required to assess its efficacy and safety profile.

Project description:BackgroundStudies on the relationship between antiepileptic drug (AED) administration and clinical outcomes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) remain scarce. Levetiracetam (LEV) is an AED that is neuroprotective in various neurologic disorders. This study aimed to determine the impact of LEV on the outcome of MELAS.MethodsA retrospective, single-center study was performed based on a large cohort of patients with MELAS with a history of seizures (n = 102). Decisions on antiepileptic therapies were made empirically. Patients were followed up for 1 to 8 years (median, 4 years) and divided into 2 groups based on whether LEV was administered (LEV or non-LEV). The modified Rankin scale (mRS) scores and mortality risks were analyzed in all patients.ResultsLEV, carbamazepine, benzodiazepines, topiramate, oxcarbazepine, valproate, and lamotrigine were administered in 48, 37, 18, 13, 11, 9, and 9 patients, singly or in combination, respectively. The mean mRS score of the LEV group (n = 48) was lower than that of the non-LEV group (n = 54; mean ± standard deviation, 2.79 ± 1.47 vs. 3.83 ± 1.93, P = 0.006) up to the end of the study. Nevertheless, there was no difference in the proportion of subjects without disability (mRS ranging 0-1) between the groups (P = 0.37). The multivariate regressions revealed that LEV treatment was associated with lower mRS scores (odds ratio 0.32, 95% confidence interval [CI] 0.15-0.68, P = 0.003) and mortality rates (hazard ratio 0.24, 95% CI 0.08-0.74, P = 0.013). There was a significant difference in the Kaplan-Meier survival curves between the groups (χ = 4.29, P = 0.04).ConclusionsThe LEV administration is associated with lower mortality in patients with MELAS in this retrospective study. Further laboratory research and prospective cohort studies are needed to confirm whether LEV has neuroprotective effects on patients with mitochondrial diseases.

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L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome.

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