Abstract
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. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres.
Highlights
Tibial muscular dystrophy (TMD, OMIM: #600334, Udd myopathy) is an autosomal dominant distal myopathy with a high prevalence in the Finnish population [1,2,3]
HSPB1 proteins are involved in the endoplasmic reticulum (ER) stress response [26], whilst HSPA5 (BIP) [27], ERN1 (IRE1) [28] and the spliced form of XBP1 [29] are involved in the unfolded protein response (UPR) pathway
Significant (P,0.05) up-regulation was observed in the expression of HSPA5 (Fig. 3A), HSPB1 (Fig. 3B), ERN1 (Fig. 3C) and the previously described UPR specific XBP1 splice isoform (Fig. 3D) in TMD samples versus controls
Summary
Tibial muscular dystrophy (TMD, OMIM: #600334, Udd myopathy) is an autosomal dominant distal myopathy with a high prevalence in the Finnish population [1,2,3]. Five other phenotypes have been reported to be associated with C-terminal titin mutations: recessive limb-girdle muscular dystrophy type 2J (LGMD2J) [2], dominant hereditary myopathy with early respiratory failure [5,6], recessive early-onset myopathy with fatal cardiomyopathy [7], core myopathy with heart disease [8] and centronuclear myopathy [9]. All Finnish TMD patients reported so far share the 11 bp deletion/insertion FINmaj founder mutation [1,2], which results in C-terminal defects in the M-line region of the sarcomeric titin protein [2]. Several other mutations in the last two exons of TTN have been shown to cause TMD in patients of other European populations [4,10,11]. TMD and LGMD2J patients do not have facial muscle weakness, dysphagia or clinically manifest cardiomyopathy. TMD muscle biopsies show myopathic–dystrophic morphology with rare fibre necrosis and frequent rimmed vacuolated fibres in affected muscles [3,12,14]
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