What is the role of degenerative processes in the pathophysiology of sporadic inclusion body myositis (s-IBM)?

Updated: Jun 08, 2018
  • Author: Michael P Collins, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Despite the preceding arguments in favor of an adaptive immune response in s-IBM, a purely autoimmune hypothesis for s-IBM is untenable because of the disease's resistance to most immunotherapy. Therefore, the alternate theory has arisen that s-IBM is a primarily degenerative disorder related to aging of the muscle, supported by the finding of abnormal, potentially pathogenic protein accumulations in myofibers.

Myofibers in s-IBM exhibit vacuolization, atrophy, abnormal myonuclei, [28, 29] and deposits of degeneration-associated proteins. Similar to actions in Alzheimer disease, myofibers in s-IBM accumulate amyloid-β (Aβ), phosphorylated tau (p-tau), apolipoprotein E, presenilin-1, the normal cellular isoform of prion protein (PrPc), and many other characteristic proteins. [30, 31, 32] Two major types of protein aggregates are found in s-IBM myofibers: (1) rounded, plaquelike, Aβ inclusion bodies; and (2) linear, squiggly, p-tau inclusions (paired helical filaments). [30, 31] Both are amyloidogenic.

In general, protein aggregation ensues from the binding of unfolded and misfolded polypeptides. [33] Unfolded and misfolded proteins, in turn, result from increased transcription, impaired disposal, abnormal crowding, or abnormal posttranslational modification of proteins, as might be induced by oxidative stress, various toxins, and aging. A specifically proposed mechanism involved in the formation of protein aggregates in s-IBM is inhibition of the ubiquitin-26S proteosome system, which is the primary degradation pathway for misfolded, unfolded, and other damaged proteins. [33, 34]

Of these various alien molecules, Aβ is putatively toxic. [35] Soluble Aβ oligomers are believed to be more cytotoxic than the insoluble β-pleated sheets. [36] Aβ accumulation results from increased synthesis and abnormal processing of amyloid precursor protein (APP) in s-IBM muscle. [37] Askanas and Engel have proposed that overexpression of APP and accumulation of toxic Aβ oligomers are early upstream events in the pathogenesis of s-IBM, predisposing to tau phosphorylation, oxidative stress, proteosomal inhibition, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and, hence, abnormal signal transduction and transcription. [38, 39] That said, the accumulation of Aβ in s-IBM myofibers has been challenged. [40]

Accumulation of unfolded or misfolded proteins in the ER triggers the unfolded protein response (UPR), which is a survival mechanism. [41, 42] The UPR comprises (1) the transcriptional induction of ER chaperone proteins to facilitate the folding, processing, and export of secretory proteins; (2) translational attenuation to reduce protein overload; and (3) increased retrotranslocation of misfolded proteins into the cytoplasm for ubiquitination and subsequent proteosomal degradation. In s-IBM muscle, expression of ER chaperone proteins is increased, colocalized with Aβ and APP, suggesting that the UPR is activated in s-IBM and promotes proper APP folding. [43] Another protective agent is heat shock protein (HSP) 70, which promotes refolding of Aβ and other misfolded or unfolded proteins. [31]

Several protein kinases are also involved in the s-IBM pathogenic cascade. Kinases that promote tau phosphorylation include cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase-3β (GSK-3β). Both Cdk5 and GSK-3β are strongly expressed in vacuolated myofibers, where they colocalize with p-tau and the paired helical filaments. [44, 30] Lithium inhibits GSK-3β and was shown to decrease tau phosphorylation in a transgenic mouse model of s-IBM. [45] Its clinical efficacy in s-IBM is now being investigated in a pilot study.

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