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31 P-MRS muscolo scheletrico

31 P-MRS muscolo scheletrico. Respirazione mitocondriale. Glicogenolisi e glicolisi. pH intracellulare (citosolico). [Mg 2+ ] libero del citosol. Metabolismo ionico. Trasporto del Pi nel mitocondrio. Efflusso di H + dal citosol. D G ATP idrolisi. ATP + H 2 O. ADP + Pi. functional

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31 P-MRS muscolo scheletrico

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  1. 31P-MRS muscolo scheletrico Respirazione mitocondriale Glicogenolisi e glicolisi pH intracellulare(citosolico) [Mg2+] libero del citosol Metabolismo ionico Trasporto del Pi nel mitocondrio Efflusso di H+ dal citosol DG ATP idrolisi

  2. ATP + H2O ADP + Pi functional ATPases PCr + ADP + H+ Cr + ATP Creatine kinase PCr + H2O Cr + Pi sum Pi PCr [ADP]

  3. Stress metabolico

  4. Respirazione mitocondriale Glicogenolisi Glicolisi Trasporto del Pi nel mitocondrio Esercizio muscolare

  5. PCr + ADP + H+ Cr + ATP

  6. work recovery 7.10 7.00 cytosolic pH 6.90 rest 6.80 6.70 60 120 0 recovery time (s)

  7. Respirazione mitocondriale Glicogenolisi Glicolisi Trasporto del Pi nel mitocondrio Recupero dall’esercizio

  8. 40 30 Y = a (1 – e ) 20 TC = 26 s t - TC 10 0 60 120 180 240 0 PCr Livello a riposo a (uniotà arbitrarie MRS) [PCr] b ultimo livello di lavoro Tempo di recupero (s)

  9. OFF 0 6 9 15 3 time (min) Glycolytic test ON CUFF REST WORK 30 RECOVERY 20 PCr (mM) 10 0

  10. 40 30 Y = b e 20 MRS arbitrary units t - TC TC = 28 s 10 0 60 120 180 240 0 Recovery time (s) [Pi] Pi resting level b last level of work

  11. work recovery 7.10 7.00 cytosolic pH 6.90 rest minimum pH 6.80 6.70 60 120 0 recovery time (s)

  12. ATP + Cr PCr + ADP + H+

  13. ATP + Cr PCr + ADP + H+

  14. work recovery 7.10 7.00 cytosolic pH 6.90 rest 6.80 6.70 60 120 0 recovery time (s) 270 J/min minimum pH 418 J/min

  15. Affinità del Carrier: (pK2 = 6.68) bassa KM for HPO42- carrier mitocondriale di Pi (rate limiting) Driving force: gradiente di pH (pH 8.0 matrice; pH 6.0 citosol) La velocità di recupero di PCr e di Pi sono inversamente proporzionali al valore di pH

  16. 80 60 TC Pi (s) (rate of PCr recovery) 40 Reference range (95% confidence interval) 20 6.2 6.4 6.6 6.8 7.0 0 Minimum pH

  17. calf muscle 31P MRS in DMD/BMD carriers

  18. Condizioni per la valutazione della velocità di recupero di PCr dall’esercizio __________ pH minimo minore di 6,90 Eccesso di substrati: Alto ADP (> 60 mM) Alto Pi (> 25 mM) Alto O2 (iperemia)

  19. 80 60 TC PCr (s) (rate of PCr recovery) 40 20 Reference range (95% confidence interval) 6.2 6.4 6.6 6.8 7.0 Minimum pH 0

  20. 80 60 TC PCr (s) (rate of PCr recovery) 40 20 Reference range (95% confidence interval) 6.2 6.4 6.6 6.8 7.0 Minimum pH mtDNA mutation at bp 117788 0

  21. 80 case 1 before training case 2 after training case 3 60 TC PCr (s) (rate of PCr recovery) 40 20 Reference range (95% confidence interval) 6.2 6.4 6.6 6.8 7.0 Minimum pH 0

  22. mitochondrial cytopathies Chronic Progressive External Ophtalmoplegia (CPEO)mtDNA deletion/s (Cox deficit), RRF Leber’s Hereditary Optic Neuropathy (LHON) 11778 bp mtDNA mutation (Complex I) Mitochondrial myopathy (MM) mtDNA deletion/s (Cox / SDH deficit), RRF Mitochondrial encephalomyopathies MEM MELAS (3243 mtDNA mutation (tRNA-leu), RRF, SCR deficit,) MERRF (Myoclonal epilespsy w. RRF) - 8993 mtDNA mutation (tRNA-lys), RRF

  23. CPEO (Cox deficit) control

  24. PCr Pi normal controlMELAS patient

  25. patients 2 3 4 5 6 7 resting Pi (mM) reference values (95% confidence interval) 2.43 4.82 controls

  26. 40 30 20 10 0 60 120 180 240 0 Control TC = 38s; pH = 6.58 CPEO (Cox deficit) PCr recovery(MRS arbitrary units) TC = 58s; pH = 6.62 Recovery time (s)

  27. 100 80 60 TC PCr (s) (rate of PCr recovery) 40 20 6.2 6.4 6.6 6.8 7.0 Minimum pH 0 Reference range (95% confidence interval)

  28. Multiple logistic regression applied to two independent indicators: 1. [Pi] at rest, 2. rate of PCr recovery 1 PrD (probability of disease) = 1 + e -(0.538 * Ds + 4.312 P – 23.729) Ds = rate of PCr recovery (sec) P = [Pi] at rest

  29. Muscle abnormality revealed by 31P-MRS Assessment condition Rest only 15/31 48.4 % Recovery only 26/31 83.9 % Analysis by multiple logistic regression 31/31 100.0 % SENSITIVITY 100%; SPECIFICITY 100%

  30. [Phosphocreatine] (mM) Phosphorylation potential (mM-1) Complicated migraine 2.91 + 0.25 39.5 Migraine with aura 3.73 + 0.30 55.3 Migraine withot aura 3.39 + 0.30 50.3 Cluster headache 3.54 + 0.36 52.1 Healty volunteers 4.45 + 0.27 83.7 HEADACHE (over 120 patients studied) (brain – occipital lobes) Failure of mitochondrial energy transductions in the brain of all patiens with headache is a favouring background for the triggering of headache

  31. skeletal muscle (gastrocnemius) HEADACHE (over 120 patients studied) Failure of skeletal muscle energy tranductions lead us to put forward the hypothesis that headache is a systemic disease primarely involving energy metabolism The rate of PCr recovery after exercise is a measure of mitochondrial funtionality dashed area defines the reference interval A = MS; B = MwA; C = MwoA; D = CH

  32. Glicogenosi muscolari

  33. glycogen UDPG PLD glucose-1-P glucose-6-P fructose-6-P fructose-1,6-P glycerldehyde-3-P (2) 3-P-glyceroyl phosphate (2) 3-P-glycerate (2) 2-P-glycerate (2) Phosphoenolpyruvate (2) Pyruvate (2) Lactate (2) McArdle

  34. glycogen UDPG PLD glucose-1-P glucose-6-P fructose-6-P patient control fructose-1,6-P glycerldehyde-3-P (2) 3-P-glyceroyl phosphate (2) 3-P-glycerate (2) 2-P-glycerate (2) Phosphoenolpyruvate (2) Pyruvate (2) Lactate (2) Deficit di PFK No pH variation during work and recovery

  35. glycogen UDPG PLD glucose-1-P glucose-6-P paziente controllo fructose-6-P fructose-1,6-P glycerldehyde-3-P (2) 3-P-glyceroyl phosphate (2) 3-P-glycerate (2) 2-P-glycerate (2) Phosphoenolpyruvate (2) Pyruvate (2) Lactate (2) Deficit di PGAM No pH variation during work and recovery

  36. Valutazione dell’effetto della terapia trattamento con CoQ pazienti con citopatie mitocondriali

  37. 5 oral CoQ (150 mg/day) for 6 months 1 100 2 9 4 3 80 7 10 6 8 60 TC PCr (s) 40 20 minimum pH 0 6.5 6.7 7.1 6.9 Mitochondrial myopathies Reference range

  38. Symptoms and clinical examination suggesting metabolic myopathy Bicycle exercise test Ischaemic test EMG Assessment of evolution Therapy follow-up Screening of families Normal 31P MRS BLOOD ANALYSIS Biochemistry, molecular genetic MUSCULAR BIOPSY Histochemistry, biochemistry, molecular genetic Abnormal Diagnosis confirmation 31P MRS

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