Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

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dc.contributor.authorAmici, David R.
dc.contributor.authorPinal-Fernandez, Iago
dc.contributor.authorMázala, Davi A. G.
dc.contributor.authorLloyd, Thomas E.
dc.contributor.authorCorse, Andrea M.
dc.contributor.authorChristopher-Stine, Lisa
dc.contributor.authorMammen, Andrew L.
dc.contributor.authorChin, Eva R.
dc.date.accessioned2021-07-21T20:42:24Z
dc.date.available2021-07-21T20:42:24Z
dc.date.issued2017-03-22
dc.description.abstractSporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca2+-regulatory proteins in IBM. Next, we investigated the Ca2+-signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca2+-regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca2+-dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca2+-activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2α phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.en_US
dc.description.urihttps://doi.org/10.1186/s40478-017-0427-7
dc.identifierhttps://doi.org/10.13016/dmiu-ry6a
dc.identifier.citationAmici, D.R., Pinal-Fernandez, I., Mázala, D.A.G. et al. Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis. acta neuropathol commun 5, 24 (2017).en_US
dc.identifier.urihttp://hdl.handle.net/1903/27561
dc.language.isoen_USen_US
dc.publisherSpringer Natureen_US
dc.relation.isAvailableAtSchool of Public Healthen_us
dc.relation.isAvailableAtKinesiologyen_us
dc.relation.isAvailableAtDigital Repository at the University of Marylanden_us
dc.relation.isAvailableAtUniversity of Maryland (College Park, MD)en_us
dc.subjectMyositisen_US
dc.subjectInclusion bodyen_US
dc.subjectMuscular diseasesen_US
dc.subjectCalciumen_US
dc.subjectCalpainen_US
dc.subjectUnfolded protein responseen_US
dc.titleCalcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositisen_US
dc.typeArticleen_US

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