Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. To identify these components we used gene expression profiling from muscle biopsies samples of TMD patients, healthy controls and from phenotypically overlapping Welander distal myopathy (WDM) patients. The profiling results were confirmed through RT-PCR and protein level analysis and we identified an activation of the unfolded protein response (UPR). UPR was then confirmed through elevation of marker genes HSPA5 (BIP) and XBP1 and the presence of ER-stress specific XBP1 splicing events. However, UPR activation appears to be insufficient, leading to build-up of ubiquitinated proteins which in turn cause activation of the autophagic system. Massive accumulation of LC3b positive autophagosomes within the rimmed vacuolated regions of degenerated muscle fibers suggests that this apparently compensatory mechanism is not capable of restoring equilibrium since these fibers degenerate further and disappear in the end stage of the pathology cascade.
