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.

• Authors: Lance H Rodan, Greg D Wells, Laura Banks, Sara Thompson, Jane E Schneiderman, Ingrid Tein
• Journal: PloS one (PLoS One) Vol. 10 Issue 5 Pg. e0127066 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25993630 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphocreatine
• phosphocreatinine
• Arginine

Topics

• Adolescent
• Arginine (pharmacology, therapeutic use)
• Case-Control Studies
• Dose-Response Relationship, Drug
• Ergometry
• Exercise (physiology)
• Female
• Humans
• MELAS Syndrome (drug therapy, metabolism, physiopathology)
• Magnetic Resonance Spectroscopy
• Male
• Muscles (drug effects, metabolism)
• Neuroimaging
• Phosphocreatine (analogs & derivatives, metabolism)
• Rest (physiology)
• Young Adult