Altered skeletal muscle (mitochondrial) properties in patients with mitochondrial DNA single deletion myopathy

Gehrig, Saskia Maria; Mihaylova, Violeta; Frese, Sebastian; Mueller, S.; Ligon‐Auer, Maria; Spengler, Christina M.; Petersen, Jens A.; Lundby, Carsten; Jung, Hans H.

doi:10.1186/s13023-016-0488-x

Cited by 21 publications

(13 citation statements)

References 53 publications

(79 reference statements)

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“…Studies on the metabolic profile of muscle fibers in patients with OXPHOS deficiency are sparse and sometimes contradictory, reporting either no fiber type predominance,21 a type I predominance,15, 43, 44, 45, 46 or a type II predominance 47. Interestingly, we found higher respiratory chain deficiency in type II fibers over type I in 5 of 6 patients.…”

Section: Discussioncontrasting

confidence: 47%

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Rocha

Rosa

Grady

et al. 2018

Annals of Neurology

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ObjectiveSingle, large‐scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large‐scale mtDNA deletions in skeletal muscle.MethodsWe investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large‐scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction.ResultsWe have defined 3 “classes” of single, large‐scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class.InterpretationCombining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex‐specific protein‐encoding genes. Furthermore, removal of mt‐tRNA genes impacts specific complexes only at high deletion levels, when complex‐specific protein‐encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130

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Section: Discussioncontrasting

confidence: 47%

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Rocha

Rosa

Grady

et al. 2018

Annals of Neurology

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“…Alterations in the mitochondrial genome change the morphology and physiology of specific tissues. In skeletal muscle, Gehrig et al () observed a fiber‐type switching from type I and more oxidative muscle fibers towards type II and more glycolytic muscle fibers in humans with mitochondrial myopathy. This type of mitochondrial defect changes the form and function of skeletal muscle leading to variations in the predominant energy sources used, increased muscle weakness, and decreased muscle health by a loss of oxidative capacity.…”

Section: Mitochondriamentioning

confidence: 99%

The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy

Theilen

Kunkel

Tyagi

2017

Journal Cellular Physiology

117

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Skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis. This arises for a multitude of reasons including the unloading of muscle during microgravity, post-surgery bedrest, immobilization of a limb after injury, and overall disuse of the musculature. The development of therapies prior to skeletal muscle atrophy settings to diminish protein degradation is scarce. Mitochondrial dysfunction is associated with skeletal muscle atrophy and contributes to the induction of protein degradation and cell apoptosis through increased levels of ROS observed with the loss of organelle function. ROS binds mtDNA, leading to its degradation and decreasing functionality. Mitochondrial transcription factor A (TFAM) will bind and coat mtDNA, protecting it from ROS and degradation while increasing mitochondrial function. Exercise stimulates cell signaling pathways that converge on and increase PGC-1α, a well-known activator of the transcription of TFAM and mitochondrial biogenesis. Therefore, in the present review we are proposing, separately, exercise and TFAM treatments prior to atrophic settings (muscle unloading or disuse) alleviate skeletal muscle atrophy through enhanced mitochondrial adaptations and function. Additionally, we hypothesize the combination of exercise and TFAM leads to a synergistic effect in targeting mitochondrial function to prevent skeletal muscle atrophy.

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“…Adicionalmente, los pacientes pueden presentar dificultades en el control de las infecciones (14) . La CPEO se manifiesta con síntomas leves en la niñez, tal como ocurrió en el paciente que reportamos (16). La debilidad muscular ocular se desarrolla gradualmente durante años e incluso décadas.…”

Section: Discussionunclassified

Neumopatía crónica secundaria al trastorno de la deglución en un paciente con miopatía mitocondrial

Palacio-Petri

Morales-Múnera

Ortiz

2019

Iatreia

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Introducción: la enfermedad pulmonar crónica secundaria a la disfagia es una complicación frecuente en los pacientes con enfermedades neuromusculares. Las miopatías mitocondriales son un conjunto de enfermedades que pueden conducir a daño pulmonar progresivo, secundario al síndrome aspirativo crónico.Caso clínico: niño de 7 años con signos clínicos y radiológicos de enfermedad pulmonar crónica; además, con desnutrición crónica, debilidad muscular, disfonía y oculoparesia externa crónica multiplanar. Su padre tuvo síntomas similares desde la infancia y requirió alimentación con dieta espesa por trastorno de la deglución. Se confirma en el paciente la presencia de disfagia como la causa de la neumopatía crónica y se sospecha miopatía congénita hereditaria. En consecuencia, se realiza el diagnóstico de enfermedad mitocondrial con oculoparesia externa crónica, mediante la secuenciación del gen polimerasa gamma del ADN mitocondrial (POLG).Conclusiones: en los pacientes con neumopatía crónica se deben considerar las enfermedades neuromusculares en el diagnóstico diferencial. La miopatía mitocondrial con oculoparesia externa crónica progresiva, se asocia con trastorno de la deglución hasta en un 50 % de los casos. El diagnóstico temprano es importante para retardar el deterioro de la función pulmonar.

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Altered skeletal muscle (mitochondrial) properties in patients with mitochondrial DNA single deletion myopathy

Cited by 21 publications

References 53 publications

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy

Neumopatía crónica secundaria al trastorno de la deglución en un paciente con miopatía mitocondrial

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