Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

AbstractSporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology.We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function.Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction.Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death.MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

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Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

PLoS ONE ◽

10.1371/journal.pone.0231064 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0231064

Author(s):

Yoshitsugu Oikawa ◽

Rumiko Izumi ◽

Masashi Koide ◽

Yoshihiro Hagiwara ◽

Makoto Kanzaki ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Inclusion Body ◽

Inclusion Body Myositis ◽

Mitochondrial Dynamics ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Mitochondrial Morphology ◽

Atp Production ◽

Bioenergetic Analysis ◽

Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

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Coexistence of TDP-43 and C5b-9 staining of muscle in a patient with inclusion body myositis

BMJ Case Reports ◽

10.1136/bcr-2020-238312 ◽

2021 ◽

Vol 14 (2) ◽

pp. e238312

Author(s):

Christina Law ◽

Huili Li ◽

Sankar Bandyopadhyay

Keyword(s):

Inclusion Body ◽

Transcriptional Repression ◽

Inclusion Body Myositis ◽

Inflammatory Myopathy ◽

Membrane Attack Complex ◽

Muscle Fibres ◽

Rimmed Vacuoles ◽

Histocompatibility Complex ◽

Immune Mediated ◽

Sporadic Inclusion Body Myositis

While sporadic inclusion body myositis (sIBM) is the most commonly acquired inflammatory myopathy above 50 years of age, its refractory response to conventional immunosuppressive treatments raises questions about its perplexing pathogenesis. Muscle biopsy typically reveals major histocompatibility complex I antigens and CD8+ T cell endomysial infiltrates invading non-necrotic muscle fibres early in the disease course with rimmed vacuoles, protein aggregates and amyloid inclusions later in the disease. Transactive response DNA-binding protein-43 (TDP-43), a protein implicated in transcriptional repression in neurodegenerative diseases, is also found in sIBM. C5b-9 membrane attack complex, an effector protein involved in the complement cascade of the immune response, is commonly found in dermatomyositis, but has rarely been reported in IBM. We describe a novel case of IBM with simultaneous C5b-9 and TDP-43 staining on quadriceps biopsy, raising the question of a possibility of concurrent immune-mediated inflammatory and myodegenerative pathogenesis.

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A Rare Case of Sporadic Inclusion Body Myositis with Atypical Presentation

Journal of Health and Allied Sciences NU ◽

10.1055/s-0041-1739230 ◽

2021 ◽

Author(s):

Manokaran Chinnusamy ◽

Sathiyanarayanan Janakiraman ◽

Ramesh Bala Arivazhagan

Keyword(s):

Inclusion Body ◽

Muscle Biopsy ◽

Inclusion Body Myositis ◽

Rare Case ◽

Immunosuppressive Agents ◽

Inflammatory Myopathy ◽

Atypical Presentation ◽

Sporadic Inclusion Body Myositis

AbstractSporadic inclusion body myositis (IBM) is the most common acquired inflammatory myopathy that occurs after the age of 50 years. IBM typically involves wrist and finger flexors and quadriceps, but all sporadic IBM may not have the classic presentation of distal arm and proximal leg involvement. Treating physicians must be aware of this atypical presentation to avoid the misdiagnosis of IBM, leading to treatment with immunosuppressive agents. The aim of this study is to increase the awareness among physicians about the atypical presentation of IBM and to emphasize the importance of muscle biopsy in such cases. Here we report a case of 52 years old male diagnosed with sporadic IBM by muscle biopsy presented with atypical presentation.

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Betekintés az idiopathiás inflammatorikus myopathiában szenvedő betegek gyógytornájába

Orvosi Hetilap ◽

10.1556/650.2016.30549 ◽

2016 ◽

Vol 157 (39) ◽

pp. 1557-1562

Author(s):

Andrea Váncsa

Keyword(s):

Randomized Controlled Trials ◽

Inclusion Body ◽

Aerobic Capacity ◽

Inclusion Body Myositis ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Muscle Performance ◽

Controlled Trials ◽

Randomized Controlled ◽

Active Disease

Using current recommended treatment, a majority of patients with idiopathic inflammatory myopathy develop muscle impairment and poor health. Beneficial effects of exercise have been reported on muscle performance, aerobic capacity and health in chronic polymyositis and dermatomyositis, as well as in active disease and inclusion body myositis to some extent. Importantly, randomized controlled trials indicate that improved health and decreased clinical disease activity could be mediated through increased aerobic capacity. Recently, reports seeking pathomechanisms of the underlying effects of exercise on skeletal muscle indicate increased aerobic capacity (i.e. increased mitochondrial capacity and capillary density, reduced lactate levels), activation of genes of aerobic phenotype and muscle growth programs and down regulation of genes related to inflammation. Exercise contributes to both systemic and within-muscle adaptations demonstrating that it is fundamental for improving muscle performance and health in patients with idiopathic inflammatory myopathy. There is a need for randomized controlled trials to study the effects of exercise in patients with active disease and inclusion body myositis. Orv. Hetil., 2016, 157(39), 1557–1562.

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Sporadic Inclusion Body Myositis: An Acquired Mitochondrial Disease with Extras

Biomolecules ◽

10.3390/biom9010015 ◽

2019 ◽

Vol 9 (1) ◽

pp. 15 ◽

Cited By ~ 3

Author(s):

Boel De Paepe

Keyword(s):

Inclusion Body ◽

Mitochondrial Disease ◽

Inclusion Body Myositis ◽

Late Onset ◽

Mitochondrial Dynamics ◽

Muscle Disorders ◽

Morphological Alterations ◽

Mitochondrial Alterations ◽

Sporadic Inclusion Body Myositis ◽

Mitochondrial Abnormality

The sporadic form of inclusion body myositis (IBM) is the most common late-onset myopathy. Its complex pathogenesis includes degenerative, inflammatory and mitochondrial aspects. However, which of those mechanisms are cause and which effect, as well as their interrelations, remain partly obscured to this day. In this review the nature of the mitochondrial dysregulation in IBM muscle is explored and comparison is made with other muscle disorders. Mitochondrial alterations in IBM are evidenced by histological and serum biomarkers. Muscular mitochondrial dynamics is disturbed, with deregulated organelle fusion leading to subsequent morphological alterations and muscle displays abnormal mitophagy. The tissue increases mitochondrial content in an attempt to compensate dysfunction, yet mitochondrial DNA (mtDNA) alterations and mild mtDNA depletion are also present. Oxidative phosphorylation defects have repeatedly been shown, most notably a reduction in complex IV activities and levels of mitokines and regulatory RNAs are perturbed. Based on the cumulating evidence of mitochondrial abnormality as a disease contributor, it is therefore warranted to regard IBM as a mitochondrial disease, offering a feasible therapeutic target to be developed for this yet untreatable condition.

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Inclusion body myositis: A distinct variety of idiopathic inflammatory myopathy

Neurology ◽

10.1212/wnl.28.1.8 ◽

1978 ◽

Vol 28 (1) ◽

pp. 8-8 ◽

Cited By ~ 214

Author(s):

S. CARPENTER ◽

G. KARPATI ◽

I. HELLER ◽

A. EISEN

Keyword(s):

Inclusion Body ◽

Inclusion Body Myositis ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Distinct Variety

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Mitochondrial DNA disturbances and deregulated expression of oxidative phosphorylation and mitochondrial fusion proteins in sporadic inclusion body myositis

Clinical Science ◽

10.1042/cs20160080 ◽

2016 ◽

Vol 130 (19) ◽

pp. 1741-1751 ◽

Cited By ~ 21

Author(s):

Marc Catalán-García ◽

Glòria Garrabou ◽

Constanza Morén ◽

Mariona Guitart-Mampel ◽

Adriana Hernando ◽

...

Keyword(s):

Mitochondrial Dna ◽

Oxidative Phosphorylation ◽

Inclusion Body ◽

Blood Cells ◽

Fusion Proteins ◽

Inclusion Body Myositis ◽

Mitochondrial Dynamics ◽

Sporadic Inclusion Body Myositis ◽

Oxphos System

In this study, we describe the role of mitochondria in sIBM, demonstrating that deregulated mitochondrial dynamics correlates with altered mtDNA stability and that the OXPHOS system is also impaired in both muscle and blood cells of these patients.

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Inclusion body myositis

10.1093/med/9780198754121.003.0011 ◽

2018 ◽

Author(s):

Pedro M. Machado

Keyword(s):

Inclusion Body ◽

Inclusion Body Myositis ◽

Inflammatory Myopathy ◽

Lymphocytic Infiltration ◽

Knee Extensors ◽

Rimmed Vacuoles ◽

Immune Mediated ◽

Sporadic Inclusion Body Myositis ◽

Muscle Disorder

Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. It is characterized by a typical early clinical phenotype with (often asymmetric) weakness of the knee extensors and finger flexors, potential involvement of pharyngeal and upper-oesophageal muscles (which may contribute to malnutrition and aspiration), and progressive and slow deterioration, which may lead to severe disability and loss of quality of life. Muscle biopsy shows chronic myopathic features, lymphocytic infiltration with invasion of non-necrotic fibres, rimmed vacuoles, mitochondrial changes, and pathological accumulation of proteins in the muscle tissue. It remains uncertain whether IBM is primarily an immune-mediated inflammatory myopathy or a degenerative myopathy with an associated inflammatory component. This chapter will describe the clinical features, natural history, investigations, current pathogenic concepts, outcome measures, and therapeutic approaches in IBM. Despite recent clues, in many respects IBM remains an unsolved mystery.

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