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Background: MELAS syndrome is associated with myopathy and exercise intolerance in addition to stroke-like episodes (SLEs). Recent work has demonstrated a beneficial effect of L-arginine therapy for treatment and prevention of SLEs. The purpose of this study was to evaluate the effects of arginine supplementation on muscle metabolism in vivo in patients with MELAS syndrome in an attempt to better understand the treatment effects of arginine. Methods:We enrolled 3 siblings with MELAS syndrome and 4 controls. We employed case control methodology for comparison of baseline exercise parameters on 31P-MRS of muscle and graded cycle ergometry. We used a clinical trial study design to assess response of these parameters to single dose and 6 week steady-state L-arginine. Results:31P MRS of muscle: At baseline, phosphocreatine (PCr) levels were elevated in MELAS subjects(p=0.05), ATP levels were decreased (p=0.01), and PCr/ATP ratio was elevated(p=0.01). The concentration of magnesium was lower in MELAS subjects (p=0.0001). Following L-arginine therapy, MELAS subjects demonstrated increased Pi/PCr with exercise (p=0.01 to 0.02), suggesting increased work capacity. One subject showed an extraordinary improvement in phosphocreatine recovery. Graded cycle ergometry: At baseline, mean percentage of VO2 max reached during exercise was lower in MELAS subjects (p=0.04). L-arginine therapy increased the percentage of maximum work at anaerobic threshold (p=0.037). Conclusions: L-arginine supplementation produces a benefit in muscle metabolism in MELAS syndrome based on laboratory exercise testing. The mechanisms underlying these improvements are not yet elucidated, and may include improved bioenergetics and/or improved perfusion.

MELAS; exercise testing; L-arginine