title: 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.
  
  
  CONCLUSIONS
  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.
  
  
  METHODS
  Class III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01603446.
authors.affiliation: Division of Neurology, Dept. of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada, M5G 1X8.
authors.forename: Lance H
authors.initials: LH
authors.lastname: Rodan
authors.affiliation: Physiology and Experimental Medicine Program, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada, M5G 1X8; Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Ont., Canada, M5G 1X8.
authors.forename: Greg D
authors.initials: GD
authors.lastname: Wells
authors.affiliation: Physiology and Experimental Medicine Program, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada, M5G 1X8; Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Ont., Canada, M5G 1X8.
authors.forename: Laura
authors.initials: L
authors.lastname: Banks
authors.affiliation: Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Ont., Canada, M5G 1X8.
authors.forename: Sara
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Physiology and Experimental Medicine Program, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada, M5G 1X8; Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Ont., Canada, M5G 1X8.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Schneiderman
authors.affiliation: Division of Neurology, Dept. of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada, M5G 1X8; Dept. of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ont., Canada, M5G 1X8.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Tein
mesh_terms: D000293:Adolescent; D001120:Arginine / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D016552:Ergometry; D015444:Exercise / Q000502:physiology*; D005260:Female; D006801:Humans; D017241:MELAS Syndrome / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D059906:Neuroimaging; D010725:Phosphocreatine / Q000031:analogs & derivatives / Q000378:metabolism; D012146:Rest / Q000502:physiology; D055815:Young Adult
chemical_list: D010725:Phosphocreatine; C025403:phosphocreatinine; D001120:Arginine