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.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests. Dr. Tein reports an operating grant from the United Mitochondrial Disease Foundation and a donation for operating funds from the Knights of Columbus, Oak Ridges Council Ontario supporting in part this study. No personal fees were obtained. The UMDF and Knights of Columbus had no role in the study design, data collection and analysis of data, decision to publish or preparation of the manuscript.

Figures

Fig 1. Flow Diagrams for the MELAS/L-arginine study (A) Consort 2010 Flow Diagram (B) Schema for MELAS/L-arginine Study Protocol.

Fig 2. A typical spectrum acquired using 31P-MRS at rest from a healthy control subject.

The peaks are representative of the concentrations of Pi, PCr and ATP. The pH and concentration of [Mg2+] can be calculated from the chemical shift between metabolites as indicated. Adapted from Pediatr Res 69 (1); pp 41, Fig 2 (2011) under a CC BY license, with permission from the Nature Publishing Group. [18]

Fig 3. Typical spectra acquired using 31P-MRS before (A) and following exercise (B) from a healthy control subject.

Note the changes in the Pi and PCr peaks. Reprinted from Pediatr Res 69 (1); pp 42, Fig 3 (2011) under a CC BY license, with permission from the Nature Publishing Group. [18]

Fig 4. Half-time of phosphocreatine (PCr) recovery (in seconds) following 5 minutes of moderate-intensity aerobic exercise protocol in MELAS subject 2 at baseline (test 1- no L-arginine) and following single-dose L-arginine (test 2) and 6 week steady-state L-arginine (test 3) therapy.