Disputats-forsvar: Tina Dysgaard Jeppesen

​Afdelingslæge Tina Dysgaard Jeppesen forsvarer sin disputats med titlen "The effect of mutated mtDNA in skeletal muscle: Insights through a series of physiological studies". 

Tidspunkt Ikon
Dato: 29-03-2019
Tid: 13:00
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​Aud. 2, opg 44, Blegdamsvej 9

Tilmelding

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Disputatsen udgår fra Copenhagen Neuromuscular Research Center, Neurologisk Klinik, Rigshospitalet. 

Assessment comitee

  • Professor Niels Tommerup (Chairman), Dr.Med.Sci., Department of Cellular and Molecular Medicine, University of Copenhagen

  • Professor Gabriele Siciliano, MD, PhD, Department of Clinical and Experimental Medicine, University of Pisa

  • Professor Professor David Gaist, MD, PhD, Department of Neurology, Odense University Hospital, University of Southern Denmark

Head of the defence

  • Professor Flemming Dela, MD, Dr.Med.Sci, Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen

Dansk resumé

Mitokondrier er organeller, der varetager slutprocessen i den aerobe metabolisme af fedt, protein og kulhydrater. Til dette formål, indeholder de en del af cellens vigtige processer såsom citronsyrecyklus og β –oksidation af fedt. Dertil er mitokondrierne en hovedfaktor i processen selvaktiveret celledød (apoptose). Mitokondrier er derved på mange områder essentiel for cellens overlevelse, og en dysfunktion af mitokondriet vil have katastrofal konsekvens for cellens funktion. Mitokondrier har deres eget DNA (mtDNA). Mutationer i mtDNA er hyppige (1:200). I 1988 blev den første patient med mtDNA associerede sygdom beskrevet, og siden da er mere end 300 patogene mtDNA mutationer blevet beskrevet. Ved at undersøge patienter med mutation i mtDNA, kan man direkte måle den fysiologiske effekt af mitokondrie dysfunktion in vivo. Med udgangspunkt i dette, udførte vi ti studier i patienter med både sporadiske og nedarvede mutationer i mtDNA. Resultaterne af studierne var: 1) At brug af cykelforsøg og 31P-MR-spektroskopi, hvor man måler ændringer i laktat, phosphokreatin, kreatin, og adenosin induceret af muskelarbejde, er diagnostisk underlegen i forhold til måling af venøs iltsaturation niveau under underarms muskelarbejde på trods af at de førstenævnte tests, har været foreslåede som diagnostiske screening tests for mitokondriesygdom; 2) At den kliniske variabilitet, som ses hos patienter med mitokondriesygdom, er direkte korreleret med mængden af muterede mtDNA kopier; En sammenhæng som ikke tidligere har været vist; 3) At den øgede iltsaturation fra arbejdende muskel, som kan måles hos patienter med mtDNA mutation, skyldes hæmmet iltekstraktion og hyperperfusion til musklen. Hyperperfusionen hos denne patientgruppe skyldes formentlig en øget frigivelse af ATP fra cirkulerende røde blodlegemer, fremfor ændring i mekanismer bag vasodilatation; 5) At det øgede laktatniveau, som kan måles under muskelarbejde hos patienter med mitokondriesygdom, ikke skyldes en reduceret evne til at oksidere laktat i musklen, men snarere en ændret produktion:omsætning relation hos patienter med mtDNA mutation sammenlignet med raske personer; 6) At selvom man producerer mindre ATP fra fedt kontra kulhydrat i forhold til det ilt der bruges, er der ingen forskel på fordelingen mellem kulhydrat:fedt omsætningen hos patienter med mtDNA mutationer sammenlignet med raske personer, på trods af reduceret oksidativ kapacitet hos patienterne med mitokondriesygdom; 7) At ændring i fedt-kulhydrat sammensætning i diæt til patienter med mitokondriesygdom ikke bedrer deres fysiske kapacitet. I stedet er aerob træning en effektiv og sikker måde hvorpå den oksidative kapacitet og dermed daglige fysiske formåen kan bedres. 

Summary English

Mitochondria are organelles that carry out the final process in the aerobic metabolism of fat, protein and carbohydrates. Thus, it contains parts of the important processes of the cell such as the citric acid cycle and β -oksidation of fat. In addition mitochondria play an important major factor in the process of self-activated cell death (apoptosis). Thus, mitochondria are essential for the survival of the cell, and dysfunction of the mitochondria can have disastrous consequence for the cell function. Mitochondria contain their own DNA (mtDNA) and mutations in mtDNA are frequent (1: 200). In 1988, the first patient with mtDNA associated disease was presented, and since then more than 300 pathogenic mtDNA mutations have been described. By examining patients with mutations in the mtDNA, it is possible to investigate the physiological effects of mitochondrial dysfunction in vivo. Based on this notion, we conducted ten studies in patients with sporadic and inherited mutations in mtDNA. The results of the studies were: 1) Cycle test and 31P-MR spectroscopy, with measurement of exercise induced changes in lactate, phosphokreatin, creatine and adenosine is diagnostic inferior to levels of venous oxygen saturation measured during forearm muscle work; 2) That the extensive clinical variability that patients with mitochondrial disease present with, is directly correlated to the amount of mutated mtDNA; A correlation that has not previously been found; 3) The increased oxygen saturation level from the exercising muscle that has been found in patients with mtDNA mutation is caused by impaired oxygen extraction and hyperperfusion to exercising muscle. This hyperperfusion is probably due to an increased release of ATP from circulating red blood cells, and not underlying changes in vasodilatation in patients with mitochondrial disease; 5) The increased lactate levels, which can be measured during exercise in patients with mitochondrial disease, is not a result of impaired ability to oxidize lactate in skeletal muscle. Instead, we found, that patients with mtDNA mutations in skeletal muscle and thus impaired oxidative capacity, have a skewed relation between production and utilization of lactate compared with healthy subjects; 6) Although oxidation of fat yields less ATP per oxygen molecule compared to oxidation of carbohydrate, patients with impaired oxidative capacity due to mtDNA mutations does not have a skewed relationship between fat and carbohydrate oxidation compared with healthy subjects; 7) Changing diet composition of the fat:carbohydrate relation in patients with mtDNA mutation does not improve physical capacity. Instead, aerobic training is an effective and safe way to improve oxidative capacity and thus daily physical ability in patients with mitochondrial disease due to mtDNA mutations.




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