Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness

Hereditary myosin myopathies are characterized by variable clinical features. Inclusion body myopathy 3 (IBM-3) is an autosomal dominant disease associated with a missense mutation (E706K) in the myosin heavy chain IIa gene. Adult patients experience progressive muscle weakness. Biopsies reveal dystrophic changes, rimmed vacuoles with cytoplasmic inclusions, and focal disorganization of myofilaments. We constructed a transgene encoding E706K myosin and expressed it in Drosophila (E701K) indirect flight and jump muscles to establish a novel homozygous organism with homogeneous populations of fast IBM-3 myosin and muscle fibers. Flight and jump abilities were severely reduced in homozygotes. ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin. Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate. Thus E706K (E701K) myosin appears far more labile than wild-type myosin. Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments. Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers. The abnormalities observed in myosin function and muscle ultrastructure likely contribute to muscle weakness observed in our flies and patients.

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Physical therapy improves motion in a patient with inclusion body myositis - a case report

Vojnosanitetski pregled ◽

10.2298/vsp171110165s ◽

2020 ◽

Vol 77 (11) ◽

pp. 1216-1220

Author(s):

Jelena Stevanovic ◽

Maja Vulovic ◽

Danijela Pavicevic ◽

Mihailo Bezmarevic ◽

Andjelka Stojkovic ◽

...

Keyword(s):

Case Report ◽

Physical Therapy ◽

Inclusion Body ◽

Muscle Weakness ◽

Muscle Biopsy ◽

Inclusion Body Myositis ◽

Clinical Symptoms ◽

Inflammatory Myopathy ◽

Functional Abilities ◽

Progressive Muscle Weakness

Introduction. Inclusion body myositis (IBM) is a rare form of inflammatory myopathy with a slowly progressive course. It is manifested by early weakness and atrophy of skeletal muscles, especially forearm muscles and the quadriceps. At the very beginning of the disease, clinical symptoms are not pronounced, therefore it is difficult to diagnose. Case report. A forty-eight-year-old female patient visited her doctor due to the weakness of muscles in arms and legs. Five years prior to this, she was treated by a neurologist and a physiatrician on several occasions with different diagnoses for progressive muscle weakness. During the last hospitalization, IBM was diagnosed after the muscle biopsy findings. After the diagnosis, the patient underwent intensive physical therapy in order to preserve the ability to independently perform everyday activities and stability of walk. Conclusion. IBM is a rare clinical entity which often takes several years to be diagnosed. Progressive muscle weakness in elderly should point to possible IBM diagnosis, which is only confirmed by muscle biopsy. Physical therapy has a significant role in the treatment as it leads to improvement of functional abilities of the patients in their daily activities, thus reducing the disability degree.

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Inclusion body myositis in twins

Neurology ◽

10.1212/wnl.51.2.598 ◽

1998 ◽

Vol 51 (2) ◽

pp. 598-600 ◽

Cited By ~ 29

Author(s):

Anthony A. Amato ◽

Robert T. Shebert

Keyword(s):

Genetic Susceptibility ◽

Inclusion Body ◽

Muscle Weakness ◽

Inclusion Body Myositis ◽

Late Onset ◽

Inclusion Body Myopathy ◽

Different Ages ◽

Sporadic Inclusion Body Myositis ◽

Volar Forearm ◽

Progressive Weakness

Sporadic inclusion body myositis (s-IBM) is characterized by late onset of slowly progressive weakness that involves the quadriceps and volar forearm muscles early in the course of the disease. There are hereditary forms of inclusion body myopathy (h-IBM) that histologically resemble s-IBM. The lack of inflammation on biopsy and the different ages at onset and patterns of muscle weakness distinguish s-IBM from h-IBM. We report twin brothers with the typical clinical and histologic features of s-IBM. The occurrence of s-IBM in these twins suggests the possibility of a genetic susceptibility to developing s-IBM.

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Dysphagia as the Presenting Symptom for Inclusion Body Myositis

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/23247096211050211 ◽

2021 ◽

Vol 9 ◽

pp. 232470962110502

Author(s):

Marcus Juan Esteban ◽

Darine Kassar ◽

Osvaldo Padilla ◽

Richard McCallum

Keyword(s):

Inclusion Body ◽

Muscle Weakness ◽

Poor Prognosis ◽

Inclusion Body Myositis ◽

Multidisciplinary Approach ◽

Oral Steroid ◽

Inflammatory Myopathies ◽

Major Improvement ◽

Presenting Symptoms ◽

Progressive Muscle Weakness

Dysphagia can be one of the manifestations of inflammatory myopathies (IMs). In some patients, it can be one of the presenting symptoms or the only symptom. We present a patient with dysphagia and progressive muscle weakness who was eventually diagnosed with inclusion body myositis (IBM). Treatment with oral steroid provided no major improvement in symptoms and thus was eventually stopped. Dysphagia in IMs is associated with complications and poor prognosis. A multidisciplinary approach is needed in its diagnosis and management as this report exemplifies.

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Manipulating Levels of Stress‐Response Proteins in a Drosophila Model of Myosin‐Based Inclusion Body Myopathy 3 Worsens Muscle Dysfunction

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.07423 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Jennifer A. Suggs ◽

Kimberley Manalo ◽

Girish C. Melkani ◽

Anju Melkani ◽

D. Brian Foster ◽

...

Keyword(s):

Stress Response ◽

Inclusion Body ◽

Muscle Dysfunction ◽

Inclusion Body Myopathy ◽

Drosophila Model ◽

Stress Response Proteins

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A Drosophila Model of Myosin-Based Inclusion Body Myopathy Type 3: Effects on Muscle Structure, Muscle Function and Aggregated Protein Profiles

Biophysical Journal ◽

10.1016/j.bpj.2014.11.1651 ◽

2015 ◽

Vol 108 (2) ◽

pp. 304a ◽

Cited By ~ 1

Author(s):

Jennifer A. Suggs ◽

Girish C. Melkani ◽

Anju Melkani ◽

Eric P. Ratliff ◽

D Brian Foster ◽

...

Keyword(s):

Inclusion Body ◽

Muscle Function ◽

Protein Profiles ◽

Inclusion Body Myopathy ◽

Muscle Structure ◽

Drosophila Model ◽

Type 3

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VCP-related Inclusion Body Myopathy Presenting with Axial Muscle Weakness

Journal of the Korean Neurological Association ◽

10.17340/jkna.2020.3.13 ◽

2020 ◽

Vol 38 (3) ◽

pp. 231-233

Author(s):

Young-Eun Park ◽

Dong-Yeong Lee ◽

Nae-Ri Kim ◽

Jin-Hong Shin ◽

Dae-Seong Kim

Keyword(s):

Inclusion Body ◽

Muscle Weakness ◽

Inclusion Body Myopathy ◽

Axial Muscle

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Biological therapy in idiopathic inflammatory myopathies

Orvosi Hetilap ◽

10.1556/oh.2014.29787 ◽

2014 ◽

Vol 155 (1) ◽

pp. 3-10

Author(s):

Levente Bodoki ◽

Melinda Nagy-Vincze ◽

Zoltán Griger ◽

Andrea Péter ◽

Csilla András ◽

...

Keyword(s):

T Cells ◽

Muscle Weakness ◽

Biological Therapy ◽

Therapeutic Options ◽

Idiopathic Inflammatory Myopathies ◽

Inflammatory Myopathies ◽

Progressive Muscle Weakness ◽

Immune Mediated ◽

Novel Therapeutic

Idiopathic inflammatory myopathies are systemic, immune-mediated diseases characterized by proximal, symmetrical, progressive muscle weakness. The aim of this work is to give an overview of the biological therapy used in the treatment of idiopathic inflammatory myopathies. The authors also focus on novel results in the therapy directed against the B- and T-cells. They emphasize the importance of new trials in these diseases which may lead to the introduction of novel therapeutic options in these disorders. Orv. Hetil., 2014, 155(1), 3–10.

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