phosphocreatine and MELAS-Syndrome

Mitochondrial dysfunction is implicated in bipolar disorder based on the following lines of evidence: 1) Abnormal brain energy metabolism measured by 31P-magnetic resonance spectroscopy, that is, decreased intracellular pH, decreased phosphocreatine (PCr), and enhanced response of PCr to photic stimulation. 2) Possible role of maternal inheritance in the transmission of bipolar disorder. 3) Increased levels of the 4977-bp deletion in mitochondrial DNA (mtDNA) in autopsied brains. 4) Comorbidity of affective disorders in certain types of mitochondrial disorders, such as autosomal inherited chronic progressive external ophthalmoplegia and mitochondrial diabetes mellitus with the 3243 mutation. Based on these findings, we searched for mtDNA mutations/ polymorphisms associated with bipolar disorder and found that 5178C and 10398A polymorphisms in mtDNA were risk factors for bipolar disorder. The 5178C genotype was associated with lower brain intracellular pH. mtDNA variations may play a part in the pathophysiology of bipolar disorder through alteration of intracellular calcium signaling systems. The mitochondrial dysfunction hypothesis, which comprehensively accounts for the pathophysiology of bipolar disorder, is proposed.

Topics: Adenosine Triphosphate; Basal Ganglia; Bipolar Disorder; Brain; Calcium Channels; DNA, Mitochondrial; Gene Deletion; Humans; MELAS Syndrome; Mitochondria; Phosphocreatine; Point Mutation; Signal Transduction

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.

Topics: Adolescent; Arginine; Case-Control Studies; Dose-Response Relationship, Drug; Ergometry; Exercise; Female; Humans; Magnetic Resonance Spectroscopy; Male; MELAS Syndrome; Muscles; Neuroimaging; Phosphocreatine; Rest; Young Adult

Localized magnetic resonance spectroscopy (MRS) yields sensitive metabolic markers to provide insight into the pathophysiology of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) in vivo. Findings in full MELAS syndrome at 1H MRS of the brain typically include severely elevated lactate and reduced N-acetylaspartate, glutamate, myo-inositol, and total creatine concentrations in stroke-like lesions. Similar but less extreme alterations are also common in gray matter (GM) regions that appear normal at magnetic resonance imaging. Phosphorus spectroscopy of peripheral muscle permits investigation of the bioenergetic status. A decline of the phosphorylation potential indicates a low energy reserve at rest. Phosphocreatine resynthesis during post-exercise recovery is delayed pointing to reduced mitochondrial capacity. As MRS is inherently non-invasive, follow-up studies can be performed to assess treatment response quantitatively.

Topics: Adenosine Triphosphate; Adolescent; Adult; Brain; Brain Chemistry; Child; Exercise; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; MELAS Syndrome; Muscle, Skeletal; Phosphocreatine; Retrospective Studies; Stroke

1H magnetic resonance spectroscopy (MRS) of the brain and (31)P MRS and saturation transfer of resting skeletal muscle were used to investigate intracellular metabolites and fluxes through the creatine kinase (CK) reaction in a patient with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Acute cortical lesions were characterized by severely elevated lactate levels and reduced concentrations of N-acetylaspartyl compounds, glutamate, and myo-inositol. Similar but less extreme alterations were also observed in gray matter regions that appeared normal on magnetic resonance images. Investigation of the gastrocnemius muscle at rest demonstrated a reduced phosphocreatine level, elevated concentrations of inorganic phosphate and free adenosine 5'-diphosphate, and an abnormally low phosphorylation potential. Besides a moderately increased muscular phosphocreatine concentration, none of the metabolic disturbances detected on MRS improved with oral creatine supplementation. Forward and reverse fluxes through the CK reaction did not significantly change upon creatine treatment. Follow-up MRS investigations may thus provide objective markers of treatment response in vivo without the hazards or inconvenience of biopsy.

Topics: Adolescent; Aspartic Acid; Brain; Creatine; Female; Glutamic Acid; Humans; Inositol; Lactic Acid; Magnetic Resonance Spectroscopy; MELAS Syndrome; Muscle, Skeletal; Phosphocreatine; Phosphorus; Phosphorylation

We studied exercise-induced changes in the adenosine triphosphate (ATP), phosphocreatine (PCr), and lactate levels in the skeletal muscle of mitochondrial patients and patients with McArdle's disease. Needle muscle biopsy specimens for biochemical measurement were obtained before and immediately after maximal short-term bicycle exercise test from 12 patients suffering from autosomal dominant and recessive forms of progressive external ophthalmoplegia and multiple deletions of mitochondrial DNA (adPEO, arPEO, respectively), five patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) 3243 A-->G point mutation, and four patients with McArdle's disease. Muscle ATP and PCr levels at rest or after exercise did not differ significantly from those of the controls in any patient group. In patients with mitochondrial disease, muscle lactate tended to be lower at rest and increase more during exercise than in controls, the most remarkable rise being measured in patients with adPEO with generalized muscle symptoms and in patients with MELAS point mutation. In McArdle patients, the muscle lactate level decreased during exercise. No correlation was found between the muscle ATP and PCr levels and the respiratory chain enzyme activity.

Topics: Adenosine Triphosphate; Adult; Aged; DNA, Mitochondrial; Electron Transport; Enzymes; Exercise; Exercise Test; Gene Deletion; Genes, Dominant; Genes, Recessive; Glycogen Storage Disease Type V; Humans; Lactic Acid; Male; MELAS Syndrome; Middle Aged; Mitochondrial Myopathies; Muscle, Skeletal; Ophthalmoplegia; Phosphocreatine; Physical Fitness

We examined brain energy metabolism by phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in the occipital cortex in a mother and a daughter with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) during photic stimulation. The peak area ratio of phosphocreatine markedly decreased during photic stimulation, and subsequently increased after the stimulation. This method, photic stimulation-31P-MRS, may be useful in assessing brain energy metabolism in neurological diseases.

Topics: Adult; Brain; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; MELAS Syndrome; Middle Aged; Phosphates; Phosphocreatine; Phosphorus Isotopes; Photic Stimulation