Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis.
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 (eIF2a 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.
Department of Kinesiology, University of Maryland College Park, College Park, MD, USA.|Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA.
David R
DR
Amici
Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA.
Iago
I
Pinal-Fernandez
Department of Kinesiology, University of Maryland College Park, College Park, MD, USA.|Children's National Health System, Children's Research Institute, Center for Genetic Medicine Research, Washington DC, USA.
Davi A G
DA
Mázala
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Thomas E
TE
Lloyd
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Andrea M
AM
Corse
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Lisa
L
Christopher-Stine
Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA. andrew.mammen@nih.gov.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. andrew.mammen@nih.gov.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. andrew.mammen@nih.gov.
Andrew L
AL
Mammen
Department of Kinesiology, University of Maryland College Park, College Park, MD, USA. erchin@umd.edu.
Eva R
ER
Chin
D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D059467:Transcriptome; D056811:Unfolded Protein Response
D009124:Muscle Proteins; D012333:RNA, Messenger; C105884:CAPN3 protein, human; D002154:Calpain; C484806:CAPN1 protein, human; D002118:Calcium
Calcium; Calpain; Inclusion body; Muscular diseases; Myositis; Unfolded protein response