Abstract
ObjectiveTo study the effects of L-arginine (L-Arg) on total body aerobic capacity and muscle metabolism as assessed by 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) in patients with MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) syndrome.MethodsWe performed a case control study in 3 MELAS siblings (m.3243A>G tRNAleu(UUR) in MTTL1 gene) with different % blood mutant mtDNA to evaluate total body maximal aerobic capacity (VO2peak) 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.ResultsAt baseline (no L-Arg), MELAS had lower serum Arg (p = 0.001). On 31P-MRS muscle at rest, MELAS subjects had increased phosphocreatine (PCr) (p = 0.05), decreased ATP (p = 0.018), and decreased intracellular Mg2+ (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 VO2peak. On 31P-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.SignificanceThese 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 EvidenceClass III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects.Trial RegistrationClinicalTrials.gov NCT01603446.
Highlights
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most common and devastating mitochondrial diseases
We found that subjects with MELAS had lower ATP levels, increased phosphocreatine (PCr) levels, and elevated PCr/ATP ratios at rest compared to controls
This is in contrast to decreased PCr levels and PCr/ATP ratios reported in the literature in mitochondrial myopathies; the latter studies were not restricted to MELAS syndrome [24]
Summary
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most common and devastating mitochondrial diseases. MELAS syndrome is associated with a myriad of neurological and systemic symptoms, including myopathy, exercise intolerance and stroke-like episodes [1]. Unique to MELAS syndrome, and presumed to underlie the stroke-like episodes, is a functional vasculopathy resulting from abnormal mitochondria in vascular smooth muscle and endothelial cells [2]. It is uncertain whether this vasculopathy plays a role in the myopathy and exercise intolerance these patients usually manifest. Recent work has demonstrated a beneficial effect of L-arginine therapy in MELAS for treatment and prevention of stroke-like episodes [3]. The mechanism (s) by which arginine effects its benefit have not been fully elucidated, it is proposed to increase nitric oxide (NO) mediated vasodilation
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