Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis
dc.contributor.author | Amici, David R. | |
dc.contributor.author | Pinal-Fernandez, Iago | |
dc.contributor.author | Mázala, Davi A. G. | |
dc.contributor.author | Lloyd, Thomas E. | |
dc.contributor.author | Corse, Andrea M. | |
dc.contributor.author | Christopher-Stine, Lisa | |
dc.contributor.author | Mammen, Andrew L. | |
dc.contributor.author | Chin, Eva R. | |
dc.date.accessioned | 2021-07-21T20:42:24Z | |
dc.date.available | 2021-07-21T20:42:24Z | |
dc.date.issued | 2017-03-22 | |
dc.description.abstract | Sporadic 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.uri | https://doi.org/10.1186/s40478-017-0427-7 | |
dc.identifier | https://doi.org/10.13016/dmiu-ry6a | |
dc.identifier.citation | Amici, 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.uri | http://hdl.handle.net/1903/27561 | |
dc.language.iso | en_US | en_US |
dc.publisher | Springer Nature | en_US |
dc.relation.isAvailableAt | School of Public Health | en_us |
dc.relation.isAvailableAt | Kinesiology | en_us |
dc.relation.isAvailableAt | Digital Repository at the University of Maryland | en_us |
dc.relation.isAvailableAt | University of Maryland (College Park, MD) | en_us |
dc.subject | Myositis | en_US |
dc.subject | Inclusion body | en_US |
dc.subject | Muscular diseases | en_US |
dc.subject | Calcium | en_US |
dc.subject | Calpain | en_US |
dc.subject | Unfolded protein response | en_US |
dc.title | Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis | en_US |
dc.type | Article | en_US |
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