Rodan Lance H, Wells Greg D, Banks Laura, Thompson Sara, Schneiderman Jane E, Tein Ingrid
Division of Neurology, Dept. of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada, M5G 1X8.
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.
PLoS One. 2015 May 20;10(5):e0127066. doi: 10.1371/journal.pone.0127066. eCollection 2015.
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.
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.
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.
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.
Class III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects.
ClinicalTrials.gov NCT01603446.
通过磷磁共振波谱法（31P-MRS）研究L-精氨酸（L-Arg）对线粒体脑肌病伴乳酸酸中毒和卒中样发作（MELAS）综合征患者全身有氧能力和肌肉代谢的影响。
我们对3名携带不同血液突变型线粒体DNA比例的MELAS同胞（MTTL1基因中m.3243A>G tRNA(leu(UUR))）进行了病例对照研究，使用分级运动试验评估全身最大有氧能力（VO(2peak)），并使用31P-MRS评估肌肉代谢。然后我们对MELAS同胞进行了一项临床试验初步研究，以评估这些参数对单剂量口服L-精氨酸和为期6周的稳态试验的反应。
在基线（未使用L-Arg）时，MELAS患者的血清精氨酸水平较低（p = 0.001）。与匹配的对照组相比，在静息状态下通过31P-MRS检测肌肉，MELAS患者的磷酸肌酸（PCr）增加（p = 0.05），三磷酸腺苷（ATP）减少（p = 0.018），细胞内镁离子（Mg(2+)）减少（p = 0.0002）。在L-精氨酸治疗后，在分级运动试验中，MELAS同胞出现了以下趋势：（1）无氧阈（AT）时平均最大工作量百分比增加；（2）AT时最大心率百分比增加；（3）VO(2peak)略有增加。在31P-MRS检测中观察到以下平均趋势：（1）运动后pH值下降变缓（酸中毒减轻）；（2）无机磷/磷酸肌酸比值（ADP）增加，提示工作能力增强；（3）中等强度运动5分钟后磷酸肌酸恢复的半衰期加快（线粒体活性标志物）；（4）扭矩增加。
这些结果表明，补充L-Arg可使MELAS患者的有氧能力和肌肉代谢得到改善。肌细胞内低镁血症是一个新发现，值得进一步研究。
L-精氨酸改善MELAS患者有氧能力和肌肉代谢的III级证据。
ClinicalTrials.gov NCT01603446。
