Résumé :
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s-IBM, the most common muscle disease of older persons, is complex and multifactorial. Aging of the muscle-fiber cellular milieu appears to be the main risk factor. Also important pathogenically are various detrimental forces within the muscle-fiber, such as "double-hit" impairment of protein disposal, endoplasmic reticulum stress, defective deacetylation, abnormal signaling and transcription, and mitochondrial abnormalities. Inhibitions of both the proteasomal and lysosomal enzymatic activities contribute to abnormal protein aggregations, _-pleated sheet amyloid accumulation, and cytoplasmic vacuolization. In s-IBM accumulation of characteristic ubiquitinated intracellular proteinacious congophilic inclusions is caused by protein unfolding/misfolding, and s-IBM is now considered a "conformational disorder". Although both muscle-fiber degeneration and mononuclear-cell inflammation are characteristic components of the s-IBM pathology, it is still unknown whether mononuclear-cell inflammation precedes muscle-fiber degeneration, or the abnormal, chemically-or configuratively- modified proteins provoke the inflammatory response. We propose that in s-IBM inflammation is secondary to the accumulation of multiple postranslationally-modified proteins that are eliciting the T-cell inflammatory reaction, because: 1) Some of the older patients with hereditary IBM (h-IBM) caused by missense mutations in the GNE gene, whose muscle biopsies have a spectrum of accumulated abnormal proteins similar to that of s-IBM, also have various degrees of lymphocytic inflammation. Therefore in older h-IBM patients it is possible that their "aging" muscle-fiber environment, makes some of the accumulated proteins interpreted as "foreign" by the immune system, thereby inducing the T-cell lymphocytic inflammation. 2) In muscle biopsies of some patients with Duchenne muscular dystrophy (DMD) caused by dystrophin mutation there is T-cell-inflammation, elicited by "revertant" dystrophin or by mini-dystrophin delivered therapeutically - both proteins are not recognized as "self" proteins by the DMD immune system, therefore inducing inflammation. 3) In contrast to usually-treatable polymyositis, which exhibits the same inflammatory pathology as s-IBM, anti-inflammatory treatments are not of sustained benefit in s-IBM. Accordingly, we propose that a unique complex intra-muscle-fiber degeneration characterized by aggregates containing several proteins - including amyloid-_ (A_) and its toxic oligomers, and phosphorylated tau - plays a primary role in the muscle-fiber destruction and disease progression. Our studies also demonstrated that ER-stress and the unfolded protein response are important aspects of the s-IBM pathogenesis, because experimentally in our IBM-human muscle culture model, ER stress induced several aspects of s-IBM pathology such as: a) activation of NF-_B, b) increase of myostatin protein and mRNA, c) decrease of SIRT1 deacetylating activity, and d) impaired autophagy. Discussed will be potential treatment avenues based on correcting these various abnormalities, including abnormal protein accumulation and misfolding. Better understanding of human muscle-fiber aging is also needed.
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