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31 P-MRS muscolo scheletrico Glicogenolisi e glicolisi Metabolismo ionico Trasporto del Pi nel mitocondrio Efflusso di H + dal citosol Respirazione mitocondriale.

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Presentation on theme: "31 P-MRS muscolo scheletrico Glicogenolisi e glicolisi Metabolismo ionico Trasporto del Pi nel mitocondrio Efflusso di H + dal citosol Respirazione mitocondriale."— Presentation transcript:

1 31 P-MRS muscolo scheletrico Glicogenolisi e glicolisi Metabolismo ionico Trasporto del Pi nel mitocondrio Efflusso di H + dal citosol Respirazione mitocondriale pH intracellulare (citosolico) [Mg 2+ ] libero del citosol G ATP idrolisi

2 ATP + H 2 OADP + Pi functional ATPases PiPCr [ADP] PCr + ADP + H + Cr + ATP Creatine kinase PCr + H 2 OCr + Pi sum

3 Stress metabolico

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7 Esercizio muscolare Respirazione mitocondriale Glicogenolisi Trasporto del Pi nel mitocondrio Glicolisi

8 PCr + ADP + H + Cr + ATP

9 cytosolic pH recovery time (s) rest workrecovery

10 Recupero dallesercizio Respirazione mitocondriale Glicogenolisi Trasporto del Pi nel mitocondrio Glicolisi

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12 Tempo di recupero (s) (uniotà arbitrarie MRS) PCr Livello a riposo a b ultimo livello di lavoro Y = a (1 – e ) - TC t TC = 26 s [PCr]

13 PCr (mM) Glycolytic test 0 10 CUFFON OFF REST RECOVERY WORK time (min)

14 Recovery time (s) MRS arbitrary units Pi resting level b last level of work Y = b e - TC t TC = 28 s [Pi]

15 cytosolic pH recovery time (s) rest workrecovery minimum pH

16 PCr + ADP + H + ATP + Cr

17 PCr + ADP + H +

18 cytosolic pH recovery time (s) rest workrecovery 418 J/min 270 J/min minimum pH

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20 La velocità di recupero di PCr e di Pi sono inversamente proporzionali al valore di pH carrier mitocondriale di Pi (rate limiting) Driving force: gradiente di pH (pH 8.0 matrice; pH 6.0 citosol) bassa K M for HPO 4 2- Affinità del Carrier: (pK2 = 6.68)

21 Minimum pH TC Pi (s) ( rate of PCr recovery ) Reference range (95% confidence interval)

22 calf muscle 31 P MRS in DMD/BMD carriers

23 Condizioni per la valutazione della velocità di recupero di PCr dallesercizio pH minimo minore di 6,90 Eccesso di substrati: Alto ADP (> 60 M) Alto Pi (> 25 mM) Alto O 2 (iperemia) __________

24 Minimum pH TC PCr (s) ( rate of PCr recovery ) Reference range (95% confidence interval)

25 Minimum pH TC PCr (s) ( rate of PCr recovery ) Reference range (95% confidence interval) mtDNA mutation at bp

26 Minimum pH TC PCr (s) ( rate of PCr recovery ) Reference range (95% confidence interval) case 1 case 2 case 3 before training after training

27 Chronic Progressive External Ophtalmoplegia (CPEO) mtDNA deletion/s (Cox deficit), RRF Lebers Hereditary Optic Neuropathy (LHON) 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) mtDNA mutation (tRNA-lys), RRF mitochondrial cytopathies

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30 CPEO (Cox deficit)control

31 normal control MELAS patient PCr Pi

32 resting Pi (mM) patients controls reference values (95% confidence interval)

33 Recovery time (s) PCr recovery (MRS arbitrary units) Control TC = 38s; pH = 6.58 TC = 58s; pH = 6.62 CPEO (Cox deficit)

34 Minimum pH Reference range (95% confidence interval) TC PCr (s) ( rate of PCr recovery ) 100

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

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

37 HEADACHE (over 120 patients studied) (brain – occipital lobes) Complicated migraine Migraine with aura Migraine withot aura Cluster headache Healty volunteers [Phosphocreatine] (mM) Phosphorylation potential (mM -1 ) Failure of mitochondrial energy transductions in the brain of all patiens with headache is a favouring background for the triggering of headache

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

39 Glicogenosi muscolari

40 McArdle UDPGPLD glycogen 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)

41 Deficit di PFK UDPGPLD glycogen 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) patientcontrol No pH variation during work and recovery

42 Deficit di PGAM UDPGPLD glycogen 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) controllo paziente No pH variation during work and recovery

43 Valutazione delleffetto della terapia trattamento con CoQ pazienti con citopatie mitocondriali

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45 Reference range minimum pH 6.9 TC PCr (s) oral CoQ (150 mg/day) for 6 months Mitochondrial myopathies

46 31 P MRS Abnormal BLOOD ANALYSIS Biochemistry, molecular genetic MUSCULAR BIOPSY Histochemistry, biochemistry, molecular genetic Normal Symptoms and clinical examination suggesting metabolic myopathy 31 P MRS Diagnosis confirmation Therapy follow-up Assessment of evolution Screening of families Bicycle exercise test Ischaemic test EMG


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