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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy

HORVATH, Rita; KEMP, John P.; TUPPEN, Helen A. L.; HUDSON, Gavin; OLDFORS, Anders; MARIE, Suely K. N.; MOSLEMI, Ali-Reza; SERVIDEI, Serenella; HOLME, Elisabeth; SHANSKE, Sara; KOLLBERG, Gittan; JAYAKAR, Parul; PYLE, Angela; MARKS, Harold M.; HOLINSKI-FEDE
Fonte: OXFORD UNIV PRESS Publicador: OXFORD UNIV PRESS
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
56.73%
Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as `benign cytochrome c oxidase deficiency myopathy` is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T > C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.; Deutsche Forschungsgemeinschaft (DFG)[HO 2505/2-1]; Academy of Medical Sciences; RVI/NGH and Newcastle upon Tyne Hospitals NHS Charity[RES0211/7262]; Wellcome Trust[074454/Z/04/Z]; BBSRC[BB/F011520/1]; United Mitochondrial Diseases Foundation; Medical Research Council (UK); UK Parkinson`s Disease Society; UK NIHR; German ministry of education and research (BMBF...

Estudo da deglutição em pacientes com miopatia mitocondrial do tipo oftalmoplegia externa crônica progressiva: avaliação clínica, manométrica e videofluoroscópica; Study of swallowing in patients with mitochondrial myopathy chronic progressive external ophthalmoplegia: clinical, manometric and videofluoroscopic evaluation.

Domenis, Danielle Ramos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/05/2008 Português
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66.73%
As miopatias mitocondriais formam um grupo de desordens clinicamente heterogêneas que podem afetar múltiplos sistemas além do músculo esquelético. A oftalmoplegia externa crônica progressiva (CPEO) é um tipo de miopatia mitocondrial que tem como características alterações nos movimentos oculares, ptose, podendo ter acometimento da musculatura facial, além de atrofia muscular de membros. A fatigabilidade precoce pode ser a queixa principal e claramente desproporcional ao grau de fraqueza e atrofia muscular detectada. A disfagia na doença é uma manifestação descrita por muitos autores, porém pouco estudada ou caracterizada. O presente estudo teve como objetivo avaliar a deglutição de pacientes com miopatia mitocondrial do tipo CPEO através de avaliação clínica, manométrica e videofluoroscópica. Para tanto, foram selecionados 14 pacientes com diagnóstico de miopatia mitocondrial do tipo CPEO, em acompanhamento no Ambulatório de Doenças Neuromusculares do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, independente de apresentarem queixas ou não quanto à alimentação. A idade variou de 15 a 62 anos, com idade média de 35,3 anos sendo 5 (35,7%) do gênero masculino e 9 (64...

Ação neuro-muscular do veneno crotálico: dados preliminares

Silva, Maria Dorvalina; Resende, Luiz Antônio L.; Ueda, Anete Kimuni; Barraviera, Benedito; Mendes, R.P.; Montenegro, Mário Rubens G.
Fonte: Academia Brasileira de Neurologia (ABNEURO) Publicador: Academia Brasileira de Neurologia (ABNEURO)
Tipo: Artigo de Revista Científica Formato: 01/nov
Português
Relevância na Pesquisa
46.62%
Estudamos 6 pacientes, 2 cães e um coelho com intoxicação crotálica. Avaliamos a condução nervosa periférica sensitiva e motora, a transmissão neuromuscular e eletromiografias. As biópsias de músculo foram processadas por histoquímica. Os 6 pacientes apresentaram mononeuropatia sensitiva no nervo periférico adjacente ao local da inoculação do veneno e encontramos evidências histoquímicas de miopatia mitocondrial. Os defeitos da transmissão neuromuscular foram mínimos. A maioria dos autores admite que veneno crotálico determina síndrome miastênica. Nossos achados indicam que ptose palpebral, facies miastênico e fraqueza muscular observados após acidente crotálico, correspondem provavelmente a miopatia mitocondrial, muitas vezes transitória e reversível.; We studied 6 patients and 2 dogs that have been bitten by South American rattlesnake Crotalus durissus terrificus and one rabbit inoculated with crotalid venom. We analized sensory and motor peripheral nerve conduction, repetitive stimulation for studying neuromuscular transmission and electromyographies. Muscle biopsies were processed by histochemistry. All patients had peripheral mononeuropathy of the closest sensitive nerve to the area of snakebite. The neuromuscular transmission alterations were minimal. Muscle histochemistry of 4 patients...

Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise

Gimenes,A.C.; Neder,J.A.; Dal Corso,S.; Nogueira,C.R.; Nápolis,L.; Mello,M.T.; Bulle,A.S.; Nery,L.E.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2011 Português
Relevância na Pesquisa
66.51%
We determined the response characteristics and functional correlates of the dynamic relationship between the rate (Δ) of oxygen consumption ( O2) and the applied power output (work rate = WR) during ramp-incremental exercise in patients with mitochondrial myopathy (MM). Fourteen patients (7 males, age 35.4 ± 10.8 years) with biopsy-proven MM and 10 sedentary controls (6 males, age 29.0 ± 7.8 years) took a ramp-incremental cycle ergometer test for the determination of the O2 on-exercise mean response time (MRT) and the gas exchange threshold (GET). The ΔO2/ΔWR slope was calculated up to GET (S1), above GET (S2) and over the entire linear portion of the response (S T). Knee muscle endurance was measured by isokinetic dynamometry. As expected, peak O2 and muscle performance were lower in patients than controls (P < 0.05). Patients had significantly lower ΔO2/ΔWR than controls...

Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy

Gimenes,A.C.; Bravo,D.M.; Nápolis,L.M.; Mello,M.T.; Oliveira,A.S.B.; Neder,J.A.; Nery,L.E.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2015 Português
Relevância na Pesquisa
66.51%
Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption ( V ˙ O 2 ) at CWR exercise...

Increased mitochondrial mass in mitochondrial myopathy mice

Wredenberg, Anna; Wibom, Rolf; Wilhelmsson, Hans; Graff, Caroline; Wiener, Heidi H.; Burden, Steven J.; Oldfors, Anders; Westerblad, Håkan; Larsson, Nils-Göran
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.83%
We have generated an animal model for mitochondrial myopathy by disrupting the gene for mitochondrial transcription factor A (Tfam) in skeletal muscle of the mouse. The knockout animals developed a myopathy with ragged-red muscle fibers, accumulation of abnormally appearing mitochondria, and progressively deteriorating respiratory chain function in skeletal muscle. Enzyme histochemistry, electron micrographs, and citrate synthase activity revealed a substantial increase in mitochondrial mass in skeletal muscle of the myopathy mice. Biochemical assays demonstrated that the increased mitochondrial mass partly compensated for the reduced function of the respiratory chain by maintaining overall ATP production in skeletal muscle. The increased mitochondrial mass thus was induced by the respiratory chain deficiency and may be beneficial by improving the energy homeostasis in the affected tissue. Surprisingly, in vitro experiments to assess muscle function demonstrated that fatigue development did not occur more rapidly in myopathy mice, suggesting that overall ATP production is sufficient. However, there were lower absolute muscle forces in the myopathy mice, especially at low stimulation frequencies. This reduction in muscle force is likely caused by deficient formation of force-generating actin–myosin cross bridges and/or disregulation of Ca2+ homeostasis. Thus...

Mitochondrial myopathy and lactic acidaemia with myoclonic epilepsy, ataxia and hypothalamic infertility: a variant of Ramsay-Hunt syndrome?

Fitzsimons, R B; Clifton-Bligh, P; Wolfenden, W H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1981 Português
Relevância na Pesquisa
46.62%
A case of mitochondrial myopathy and lactic acidaemia with myoclonic epilepsy, cerebellar ataxia and high-tone hearing loss is presented. There was no ptosis or ophthalmoplegia. Endocrine investigations showed a defect in hypothalamic function which was a likely cause of infertility. The case is compared with previously reported examples of mitochondrial myopathy with myoclonic epilepsy, and contrasted with the Kearns-Sayre syndrome. It is concluded that mitochondrial myopathy, myoclonic epilepsy and ataxia may be distinguishing features of a specific familial disease, which on presentation may mimic the Ramsay-Hung syndrome.

Mitochondrial myopathy: a genetic study of 71 cases.

Harding, A E; Petty, R K; Morgan-Hughes, J A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1988 Português
Relevância na Pesquisa
46.58%
Of 71 index cases with histologically defined mitochondrial myopathy, 13 (18%) had relatives who were definitely affected with a similar disorder. Eight familial cases from four families were confined to a single generation. In five families maternal transmission to offspring occurred. There were no instances of paternal transmission, but one patient had an affected cousin in the paternal line. No consistent clinical syndrome or pattern of inheritance emerged for any identified defect of the mitochondrial respiratory chain, localised biochemically in 41 cases. Overall, the recurrence rate was 3% for sibs and 5.5% for offspring of index cases. Review of published reports of familial cases of mitochondrial myopathy suggests that the ratio of maternal to paternal transmission is about 9:1. We conclude that these disorders may be caused by mutations of either nuclear or mitochondrial genes.

Familial visceral myopathy associated with a mitochondrial myopathy.

Lowsky, R; Davidson, G; Wolman, S; Jeejeebhoy, K N; Hegele, R A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1993 Português
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46.66%
A 27 year old man with intestinal pseudo-obstruction who developed parenteral nutrition induced hyperlipidaemia and who also had ophthalmoplegia and an undifferentiated myopathy is described. Histological examination of biopsy specimens and molecular analysis show that this patient had both familial visceral myopathy and a mitochondrial myopathy, suggesting that a mitochondrial DNA mutation is the molecular lesion in familial visceral myopathy.

Adult-onset mitochondrial myopathy.

Fernandez-Sola, J.; Casademont, J.; Grau, J. M.; Graus, F.; Cardellach, F.; Pedrol, E.; Urbano-Marquez, A.
Fonte: BMJ Group Publicador: BMJ Group
Tipo: Artigo de Revista Científica
Publicado em /03/1992 Português
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46.72%
Mitochondrial diseases are polymorphic entities which may affect many organs and systems. Skeletal muscle involvement is frequent in the context of systemic mitochondrial disease, but adult-onset pure mitochondrial myopathy appears to be rare. We report 3 patients with progressive skeletal mitochondrial myopathy starting in adult age. In all cases, the proximal myopathy was the only clinical feature. Mitochondrial pathology was confirmed by evidence of ragged-red fibres in muscle histochemistry, an abnormal mitochondrial morphology in electron microscopy and by exclusion of other underlying diseases. No deletions of mitochondrial DNA were found. We emphasize the need to look for a mitochondrial disorder in some non-specific myopathies starting in adult life.

Cardiac scintigraphic findings of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: A case report

Matsuo, Shinro; Nakajima, Kenichi; Kinuya, Seigo; Sato, Yuichi; Matsumoto, Naoya; Horie, Minoru
Fonte: Pulsus Group Inc Publicador: Pulsus Group Inc
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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46.55%
A 49-year-old woman was admitted to hospital because of heart failure. She was diagnosed as having mitochondrial cardiomyopathy and diabetes mellitus. Echocardiography revealed a hypertrophic and poorly contracting left ventricle. A diagnosis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes was established by muscle biopsy. She underwent technetium-99m-sestamibi (99mTc-MIBI) and beta-methyl-p-123I-iodophenyl-pentadecanoic acid (123I-BMIPP) scintigraphic examinations. 99mTc-MIBI single-photon emission computed tomography revealed reduced tracer uptake in the hypertrophic left ventricular inferior wall. In contrast, there was an increase in 123I-BMIPP uptake in the in the region of reduced 99mTc-MIBI uptake (99mTc-MIBI/123I-BMIPP mismatch). There was rapid washout of 99mTc-MIBI from the myocardium (washout rate increased by 30%). Decreased 99mTc-MIBI and increased 123I-BMIPP uptake (99mTc-MIBI/123I-BMIPP mismatch) were the characteristics of cardiac involvement in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.

Activation of the PPAR/PGC-1α pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype

Wenz, Tina; Diaz, Francisca; Spiegelman, Bruce M.; Moraes, Carlos T.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2008 Português
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46.64%
Neuromuscular disorders with defects in the mitochondrial ATP generating system affect a large number of children and adults worldwide, but remain without treatment. We used a mouse model of mitochondrial myopathy, caused by a cytochrome c oxidase deficiency, to evaluate the effect of induced mitochondrial biogenesis on the course of the disease. Mitochondrial biogenesis was induced either by transgenic expression of peroxisome proliferator activated receptor γ (PPARγ) coactivator α (PGC-1α) in skeletal muscle or by administration of bezafibrate, a PPAR pan-agonist. Both strategies successfully stimulated residual respiratory capacity in muscle tissue. Mitochondrial proliferation resulted in an enhanced OXPHOS capacity per muscle mass. As a consequence, ATP levels were conserved resulting in a delayed onset of the myopathy and a markedly prolonged live span. Thus, induction of mitochondrial biogenesis through pharmacological or metabolic modulation of the PPAR/PGC-1α pathway promises to be an effective therapeutic approach for mitochondrial disorders.

Mice Lacking TR4 Nuclear Receptor Develop Mitochondrial Myopathy with Deficiency in Complex I

Liu, Su; Lee, Yi-Fen; Chou, Samuel; Uno, Hideo; Li, Gonghui; Brookes, Paul; Massett, Michael P.; Wu, Qiao; Chen, Lu-Min; Chang, Chawnshang
Fonte: Endocrine Society Publicador: Endocrine Society
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.66%
The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human mitochondrial disease cases still remain unclear. Here we report that mice lacking testicular nuclear receptor 4 (TR4−/−) suffered mitochondrial myopathy, and histological examination of TR4−/− soleus muscle revealed abnormal mitochondrial accumulation. In addition, increased serum lactate levels, decreased mitochondrial ATP production, and decreased electron transport chain complex I activity were found in TR4−/− mice. Restoration of TR4 into TR4−/− myoblasts rescued mitochondrial ATP generation capacity and complex I activity. Further real-time PCR quantification and promoter studies found TR4 could modulate complex I activity via transcriptionally regulating the complex I assembly factor NDUFAF1, and restoration of NDUFAF1 level in TR4−/− myoblasts increased mitochondrial ATP generation capacity and complex I activity. Together, these results suggest that TR4 plays vital roles in mitochondrial function, which may help us to better understand the pathogenesis of mitochondrial myopathy, and targeting TR4 via its ligands/activators may allow us to develop better therapeutic approaches.

Increased capillaries in mitochondrial myopathy: implications for the regulation of oxygen delivery

Taivassalo, Tanja; Ayyad, Karen; Haller, Ronald G.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.68%
Human skeletal muscle respiratory chain defects restrict the ability of working muscle to extract oxygen from blood, and result in a hyperkinetic circulation during exercise in which oxygen delivery is excessive relative to oxygen uptake and oxygen levels within contracting muscle are abnormally high. To investigate the role of the muscle microcirculation in this anomalous circulatory response and possible implications for the regulation of muscle angiogenesis, we assessed muscle oxidative capacity during cycle exercise and determined capillary levels and distribution and vascular endothelial growth factor expression in quadriceps muscle biopsies in patients with mitochondrial myopathy attributable to heteroplasmic mitochondrial DNA mutations. We found that in patients with mitochondrial myopathy, muscle capillary levels were twice that of sedentary healthy subjects (3.0 ± 0.9% compared with 1.4 ± 0.3%, P < 0.001) despite the fact that oxygen utilization during peak cycle exercise was half that of control subjects (11.1 ± 4.0 ml/kg/min compared with 20.7 ± 7.9 ml/kg/min, P < 0.01); that capillary area was greatest in patients with the most severe muscle oxidative defects and was more than two times higher around muscle fibre segments with defective (i.e. cytochrome oxidase negative/succinic dehydrogenase-positive or ‘ragged-red’ fibres) compared with more preserved respiratory chain function; and that vascular endothelial growth factor expression paralleled capillary distribution. The increased muscle capillary levels in patients correlated directly (r2 = 0.68...

Partial tandem duplication of mtDNA–tRNAPhe impairs mtDNA translation in late-onset mitochondrial myopathy

Arzuffi, Paola; Lamperti, Costanza; Fernandez-Vizarra, Erika; Tonin, Paola; Morandi, Lucia; Zeviani, Massimo
Fonte: Pergamon Press Publicador: Pergamon Press
Tipo: Artigo de Revista Científica
Publicado em /01/2012 Português
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46.62%
An 80-year-old woman (PI) has been suffering of late onset progressive weakness and wasting of lower-limb muscles, accompanied by high creatine kinase levels in blood. A muscle biopsy, performed at 63 years, showed myopathic features with partial deficiency of cytochrome c oxidase. A second biopsy taken 7 years later confirmed the presence of a mitochondrial myopathy but also of vacuolar degeneration and other morphological features resembling inclusion body myopathy. Her 46-year-old daughter (PII) and 50-year-old son (PIII) are clinically normal, but the creatine kinase levels were moderately elevated and the EMG was consistently myopathic in both. Analysis of mitochondrial DNA sequence revealed in all three patients a novel, homoplasmic 15 bp tandem duplication adjacent to the 5′ end of mitochondrial tRNAPhe gene, encompassing the first 11 nucleotides of this gene and the four terminal nucleotides of the adjacent D-loop region. Both mutant fibroblasts and cybrids showed low oxygen consumption rate, reduced mitochondrial protein synthesis, and decreased mitochondrial tRNAPhe amount. These findings are consistent with an unconventional pathogenic mechanism causing the tandem duplication to interfere with the maturation of the mitochondrial tRNAPhe transcript.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes unveiled by valproate

Chaudhry, Neera; Patidar, Yogesh; Puri, Vinod
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
Relevância na Pesquisa
46.55%
Valproic acid (VPA) is widely used as an anti-epileptic drug. The primary mechanism of VPA toxicity is interference with mitochondrial beta-oxidation, and it can exacerbate an underlying mitochondrial cytopathy. We report a case of Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes unmasked by use of Sodium Valproate in a 12-year-old boy who presented with headache and seizures. There was precipitation of encephalopathy, myopathy, lactic acidosis, and hepatic damage within two days of valproate use, after withdrawing of which there was a remarkable clinical and biochemical recovery.

Endurance exercise is protective for mice with mitochondrial myopathy

Wenz, Tina; Diaz, Francisca; Hernandez, Dayami; Moraes, Carlos T.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
Publicado em /05/2009 Português
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46.84%
Defects in the mitochondrial ATP-generating system are one of the most commonly inherited neurological disorders, but they remain without treatment. We have recently shown that modulation of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) level in skeletal muscle of a mitochondrial myopathy mouse model offers a therapeutic approach. Here we analyzed if endurance exercise, which is known to be associated with an increased PGC-1α level in muscle, offers the same beneficial effect. We subjected male and female mice that develop a severe mitochondrial myopathy due to a cytochrome-c oxidase deficiency at 3 mo of age to endurance exercise training and monitored phenotypical and metabolic changes. Sedentary myopathy and wild-type mice were used as controls. Exercise increased PGC-1α in muscle, resulting in increased mitochondrial biogenesis, and successfully stimulated residual respiratory capacity in muscle tissue. As a consequence, ATP levels were increased in exercised mice compared with sedentary myopathy animals, which resulted in a delayed onset of the myopathy and a prolonged lifespan of the exercised mice. As an added benefit, endurance exercise induced antioxidant enzymes. The overall protective effect of endurance exercise delayed the onset of the mitochondrial myopathy and increased life expectancy in the mouse model. Thus stimulating residual oxidative phosphorylation function in the affected muscle by inducing mitochondrial biogenesis through endurance exercise might offer a valuable therapeutic intervention for mitochondrial myopathy patients.

Axial mitochondrial myopathy in a patient with rapidly progressive adult-onset scoliosis

Hiniker, Annie; Wong, Lee-Jun; Berven, Sigurd; Truong, Cavatina K; Adesina, Adekunle M; Margeta, Marta
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 16/09/2014 Português
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46.76%
Axial myopathy can be the underlying cause of rapidly progressive adult-onset scoliosis; however, the pathogenesis of this disorder remains poorly understood. Here we present a case of a 69-year old woman with a family history of scoliosis affecting both her mother and her son, who over 4 years developed rapidly progressive scoliosis. The patient had a history of stable scoliosis since adolescence that worsened significantly at age 65, leading to low back pain and radiculopathy. Paraspinal muscle biopsy showed morphologic evidence of a mitochondrial myopathy. Diagnostic deficiencies of electron transport chain enzymes were not detected using standard bioassays, but mitochondrial immunofluorescence demonstrated many muscle fibers totally or partially deficient for complexes I, III, IV-I, and IV-IV. Massively parallel sequencing of paraspinal muscle mtDNA detected multiple deletions as well as a 40.9% heteroplasmic novel m.12293G > A (MT-TL2) variant, which changes a G:C pairing to an A:C mispairing in the anticodon stem of tRNA LeuCUN. Interestingly, these mitochondrial abnormalities were not detected in the blood of either the patient or her son, suggesting that the patient’s rapidly progressive late onset scoliosis was due to the acquired paraspinal mitochondrial myopathy; the cause of non-progressive scoliosis in the other two family members currently remains unexplained. Notably...

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3

Khan, Nahid A; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J; Auwerx, Johan; Suomalainen, Anu
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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46.66%
Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD+/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD+ precursor, was previously shown to boost NAD+ levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD+ levels are a promising treatment strategy for mitochondrial myopathy.

When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

Lorenzoni,Paulo José; Werneck,Lineu Cesar; Kay,Cláudia Suemi Kamoi; Silvado,Carlos Eduardo Soares; Scola,Rosana Herminia
Fonte: Academia Brasileira de Neurologia - ABNEURO Publicador: Academia Brasileira de Neurologia - ABNEURO
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/11/2015 Português
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46.55%
ABSTRACTMitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.