phosphocreatine and Retinitis-Pigmentosa

Phosphorus magnetic resonance spectroscopy (31P-MRS) was used to study in vivo the energy metabolism of brain and skeletal muscle in two members of an Italian pedigree with NARP syndrome due to a point mutation at bp 8993 of mtDNA. In the youngest patient, a 13 year old girl with retinitis pigmentosa, ataxia, and psychomotor retardation, there was an alteration of brain energy metabolism shown by a decreased phosphocreatine content, increased [ADP] and decreased phosphorylation potential. The energy metabolism of her skeletal muscle was also abnormal, as shown by resting higher inorganic phosphate and lower phosphocreatine concentrations than in normal subjects. Her mother, a 41 year old woman with minimal clinical involvement, showed a milder derangement of brain energy metabolism and normal skeletal muscle. Findings with MRS showed that this point mutation of mtDNA is responsible for a derangement of energy metabolism in skeletal muscle and even more so in the brain.

Topics: Adenosine Diphosphate; Adolescent; Adult; Ataxia; Brain; Brain Chemistry; Case-Control Studies; DNA, Mitochondrial; Energy Metabolism; Female; Follow-Up Studies; Humans; Intellectual Disability; Magnetic Resonance Spectroscopy; Muscles; Pedigree; Phosphocreatine; Phosphorus Isotopes; Phosphorylation; Point Mutation; Retinitis Pigmentosa; Syndrome

We determined the metabolic changes that precede cell death in the dystrophic proline-23-histidine (P23H) line 3 (P23H-3) rat retina compared with the normal Sprague-Dawley (SD) rat retina. Metabolite levels and metabolic enzymes were analyzed early in development and during the early stages of degeneration in the P23H-3 retina. Control and degenerating retinas showed an age-dependent change in metabolite levels and enzymatic activity, particularly around the time when phototransduction was activated. However, lactate dehydrogenase (LDH) activity was significantly higher in P23H-3 than SD retina before the onset of photoreceptor death. The creatine/phosphocreatine system did not contribute to the increase in ATP, because phosphocreatine levels, creatine kinase, and expression of the creatine transporter remained constant. However, Na(+)-K(+)-ATPase and Mg(2+)-Ca(2+)-ATPase activities were increased in the developing P23H-3 retina. Therefore, photoreceptor apoptosis in the P23H-3 retina occurs in an environment of increased LDH, ATPase activity, and higher-than-normal ATP levels. We tested the effect of metabolic challenge to the retina by inhibiting monocarboxylate transport with alpha-cyano-4-hydroxycinnamic acid or systemically administering the phosphodiesterase inhibitor sildenafil. Secondary to monocarboxylate transport inhibition, the P23H-3 retina did not demonstrate alterations in metabolic activity. However, administration of sildenafil significantly reduced LDH activity in the P23H-3 retina and increased the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end-labeled photoreceptor cells. Photoreceptor cells with a rhodopsin mutation display an increase in apoptotic markers secondary to inhibition of a phototransduction enzyme (phosphodiesterase), suggesting increased susceptibility to altered cation entry.

Topics: Adenosine Triphosphate; Age Factors; Animals; Apoptosis; Ca(2+) Mg(2+)-ATPase; Coumaric Acids; Creatine; Creatine Kinase; Disease Models, Animal; Disease Progression; Energy Metabolism; Histidine; L-Lactate Dehydrogenase; Membrane Transport Proteins; Monocarboxylic Acid Transporters; Mutation; Phosphocreatine; Phosphodiesterase Inhibitors; Piperazines; Proline; Purines; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Retina; Retinitis Pigmentosa; Sensory Rhodopsins; Sildenafil Citrate; Sodium-Potassium-Exchanging ATPase; Sulfones

In gyrate atrophy of the choroid and retina with hyperornithinaemia (GA), inherited deficiency of ornithine-o-aminotransferase leads to progressive fundus destruction and atrophy of type II skeletal muscle fibres. Because high ornithine concentrations inhibit creatine biosynthesis, the ensuing deficiency of high-energy creatine phosphate may mediate the pathogenesis.. Relative concentrations of inorganic phosphate (Pi), creatine phosphate (PCr) and ATP in resting calf muscle were recorded in 23 GA patients and 33 control subjects using 31P-magnetic resonance spectroscopy (MRS). Eight patients with autosomal recessive retinitis pigmentosa with matched control subjects constituted an additional reference group.. The PCr/Pi and PCr/ATP ratios (means +/- SD) were lower for the GA patients than for healthy control subjects [4.66 +/- 0.37 vs. 9.75 +/- 2.17 (P < 0.0001) and 2.85 +/- 0.37 vs. 3.70 +/- 0.50 (P < 0.05) respectively]. In retinitis pigmentosa the respective values were 9.12 +/- 2.57 and 4.25 +/- 0.45. Age and stage of the disease had no effect.. Muscle 31P-MRS spectra were markedly abnormal in all GA patients.

Topics: Adenosine Triphosphate; Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Female; Gyrate Atrophy; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphates; Phosphocreatine; Phosphorus Isotopes; Retinitis Pigmentosa

Phosphorus magnetic resonance spectroscopy (31P-MRS) has emerged as a noninvasive reliable tool for in vivo study of human tissue bioenergetics. It detects and quantifies some phosphorylated compounds present in millimolar concentration inside the cell, including ATP, phosphocreatine (PCr) and inorganic phosphate (Pi). By 31P-MRS we studied brain and skeletal muscle energy metabolism of three patients with retinitis pigmentosa before and after oral coenzyme Q10 (CoQ10) (100 mg/day). Before treatment we found a low PCr content in the brains of all patients, accompanied by a high [Pi] and high [ADP]. In two of three patients CoQ10 treatment resulted in a larger brain energy reserve mainly shown by an increased [PCr]. Abnormal muscle mitochondrial function was found only in one patient as shown by a reduced rate of PCr resynthesis after exercise. In this patient CoQ10 treatment resulted in an increased rate of PCr resynthesis. Our observations indicate that CoQ10 can improve mitochondrial functionality in the brain and skeletal muscle of patients with retinitis pigmentosa.

Topics: Adenosine Triphosphate; Adolescent; Adult; Coenzymes; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria, Muscle; Phosphates; Phosphocreatine; Phosphorus Isotopes; Retinitis Pigmentosa; Ubiquinone; Visual Cortex