Mitochondrial pathology in inclusion body myositis
Introduction
Sporadic inclusion body myositis (IBM) is an idiopathic inflammatory myopathy that causes progressive muscle weakness and atrophy, predominantly affecting quadriceps and long finger flexors, and dysphagia is common [1], [2], [3], [4]. IBM is the most common inflammatory muscle disease in patients over 50 years of age, one study showed a prevalence of 51 cases per million inhabitants in this age group [5]. However, the pathogenesis remains enigmatic, and no therapies have yet proven effective [1], [6], [7]. Morphological findings in IBM muscle fibers include atrophy, rimmed vacuoles, ragged red fibers, cytochrome c oxidase (COX) deficiency and infiltration of mononuclear inflammatory cells. Eventually the muscle is replaced by fat and fibrous connective tissue.
Occasional COX-deficient muscle fibers can be found in normal aging [8], but patients with IBM display a larger amount of such fibers than age-matched controls [9]. A recent study from Rygiel et al. showed that fibers with respiratory deficiency were more prone to be atrophic and therefore of pathogenic importance [10]. COX-deficient fibers are the second most common histopathological finding in IBM patients [11], being 100% sensitive and 73% specific for IBM in inflammatory myopathy without rimmed vacuoles [12] and they are associated with somatic deletions in mtDNA [8], [9], [10].
An accelerated aging process in muscle has been discussed as a part of the pathogenesis in IBM [9], [13], [14], [15]. Variants in genes encoding for proteins associated with mtDNA maintenance such as mitochondrial DNA polymerase gamma (POLG) [14] and Twinkle (C10orf2) (RJ Wiesner, personal communication) have been shown to induce a mitochondrial ageing phenotype in mice by causing somatic mtDNA mutations.
Mitochondrial DNA polymerase gamma is the only known polymerase to replicate and repair mtDNA, and the catalytical part is encoded by POLG. Many pathogenic POLG variants are characterized by multiple mtDNA deletions and disruption of mitochondrial function in post-mitotic tissues. POLG contains a CAG trinucleotide repeat, which normally consists of 10 or 11 repeats, encoding a poly-Q tract [16], [17]. It has been shown that abnormal length of the POLG CAG repeat is associated with Parkinson's disease in Sweden and Finland [16], [18], and a meta-analysis has confirmed an association between non-10Q-alleles and Parkinson's disease [17].
Variants in additional nuclear DNA (nDNA) genes, which regulate transcription, replication and maintenance of mtDNA, can cause accumulation of somatic mtDNA deletions leading to human disease. They include C10orf2 (Twinkle), DNA2 [19], MGME1 (earlier C20orf72) [20], POLG2 and OPA1 [21]. An imbalance in the mitochondrial deoxyribonucleotide (dNTP) pools, which may be caused by variants in TYMP, RRM2B [22] and SLC25A4 (ANT1) [23] can also result in mtDNA deletions and disease [22], [24].
In this study, we wished to examine if IBM is associated with sequence variants in these genes. We also aimed to confirm the association between COX-deficient muscle fibers and mtDNA deletions.
Section snippets
Patients and morphology
From a register of approximately 150 patients diagnosed with IBM at Sahlgrenska University Hospital in Gothenburg, Sweden, fresh frozen muscle specimens were examined regarding the amount of COX-deficient muscle fibers as previously described [25]. The patients were included in the study if they had typical clinical symptoms and morphology for IBM including inflammation, rimmed vacuoles and positive staining for p62/Sequestosome1, and either very few or very numerous COX-deficient fibers (Fig. 1
Analysis of mtDNA in muscle
LX-PCR analysis of mtDNA extracted from muscle tissue demonstrated multiple mtDNA deletions in the mtDNA major arc in thirteen of fifteen patients in the group with a large proportion of COX-deficient fibers, compared with one of eleven patients in the group with a low proportion (Supplementary Table S1). No patients disclosed deletions in the minor arc, and a portion of the ND1-gene could thus be used as a target to measure the total amount of mtDNA by qPCR.
The relative amount of mtDNA
Discussion
The pathogenesis of IBM is still unknown, but mitochondrial alterations are frequently encountered. In this study, we show that the percentage of COX-deficient muscle fibers correlates to the relative amount of mtDNA deletions. We further demonstrate that eight of the 26 studied IBM patients carry heterozygous POLG variants, including a previously not reported missense variant. There was no association between non-10/11 CAG repeats in POLG and IBM in our cohort. Furthermore, we found a
Acknowledgments
The authors are grateful to Gabriella Almén and Anna-Carin Ericson for skilled methodical and technical assistance and Kirsten Mehlig for statistical advice. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the
References (41)
- et al.
Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches
Lancet Neurol
(2007) - et al.
Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis
J Clin Neurosci
(2008) - et al.
Inclusion body myositis: morphological clues to correct diagnosis
Neuromuscul Disord
(2002) - et al.
Variations of the CAG trinucleotide repeat in DNA polymerase gamma (POLG1) is associated with Parkinson's disease in Sweden
Neurosci Lett
(2010) - et al.
Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population
Mitochondrion
(2012) - et al.
POLG1 polyglutamine tract variants associated with Parkinson's disease
Neurosci Lett
(2010) - et al.
Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability
Am J Hum Genet
(2013) - et al.
Mitochondrial DNA depletion syndromes–many genes, common mechanisms
Neuromuscul Disord
(2010) - et al.
Inclusion body myositis. Clinical features and clinical course of the disease in 64 patients
J Neurol
(2005) - et al.
A 12-year follow-up in sporadic inclusion body myositis: an end stage with major disabilities
Brain
(2011)
Long-term observational study of sporadic inclusion body myositis
Brain
Pathogenesis and therapy of inclusion body myositis
Curr Opin Neurol
Diagnosis, pathogenesis and treatment of inclusion body myositis
Curr Opin Neurol
Mitochondrial abnormalities in inclusion-body myositis
Neurology
Mitochondrial DNA deletions in inclusion body myositis
Brain
Mitochondrial and inflammatory changes in sporadic inclusion body myositis
Neuropathol Appl Neurobiol
A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis
BMJ Open
Mitochondrial DNA deletions in muscle fibers in inclusion body myositis
J Neuropathol Exp Neurol
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Nature
Analysis of multiple mitochondrial DNA deletions in inclusion body myositis
Hum Mutat
Cited by (28)
Inclusion body myositis: The interplay between ageing, muscle degeneration and autoimmunity
2022, Best Practice and Research: Clinical RheumatologyCitation Excerpt :Mitochondria are essential for ATP generation, and mitochondrial dysfunction has been linked to a large number of metabolic and muscle diseases. IBM muscle features mitochondrial abnormalities including a higher proportion of COX negative fibres, ragged red fibres and mitochondrial DNA (mtDNA) deletions compared to healthy aged-matched samples [7,29]. In many neurodegenerative diseases, cellular stress, such as that caused by protein aggregation, can lead to mitochondrial toxicity and activation of the mitochondrial permeability transition pore (mPTP) [30].
Mitochondrial DNA depletion in sporadic inclusion body myositis
2019, Neuromuscular DisordersCitation Excerpt :MtDNA deletions in sIBM are similar to those seen in normal aging and in autosomally inherited external opthalmoplegia suggesting a similar mechanism [12]. There are also rare reports of mtDNA depletion and dysregulation of Krebs cycle and respiratory chain proteins [13] and variants in nuclear mitochondrial genes such as POLG and RRM2B have been recorded [10]. While there is considerable evidence of mitochondrial dysfunction and especially mtDNA abnormalities in sIBM, mtDNA deletions have not been seen in all patients [8].
Sporadic inclusion-body myositis: Recent advances and the state of the art in 2016
2016, Revue NeurologiqueCitation Excerpt :At present, only a few of these efforts have identified genes potentially involved in sIBM pathogenesis [29], namely, genes located in MHC regions and those involved in mtRNA maintenance or protein homeostasis. A good example of the pathological course and entanglement of impaired genes is reflected by the correlation between the amount of COX-deficient fibers and proportion of deleted mtDNA [11,12]. In the years to come, studies of transcriptome profiling and expression quantitative trait loci (eQRLs) in sIBM may possibly be considered by application of RNA sequencing in muscle tissues and lymphoblast lines.
Idiopathic inflammatory myositis
2016, Best Practice and Research: Clinical RheumatologyCitation Excerpt :A variable inflammatory response comprising CD8+ lymphocytes and macrophages invading major histocompatibility complex (MHC) class 1 immunolabelled myofibres is present. The number of myofibres deficient in cytochrome oxidase (COX negative) is greater than that expected for age [87], and it is associated with mitochondrial dysfunction, recently shown to be secondary to multiple acquired deletions in mitochondrial DNA [88]. Electron microscopy characteristically reveals 15–20-nm filamentous cytoplasmic (occasionally nuclear) inclusions, although the absence of these filaments does not exclude a diagnosis of IBM.
Sporadic Inclusion Body Myositis at the Crossroads between Muscle Degeneration, Inflammation, and Aging
2024, International Journal of Molecular Sciences