Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

Abstract

Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis.

Derepressing muscleblind expression by miRNA sponges ameliorates myotonic dystrophy-like phenotypes in Drosophila

“…Firstly, administration of recombinant Mbnl1 protein to a HSA LR mouse model of DM1, rescues myotonia and the splicing alterations characteristic of DM126. Secondly, we showed that the overexpression of a muscleblind isoform partially rescues muscle atrophy in a Drosophila DM1 model27. Finally, MBNL1 overexpression is well tolerated in skeletal muscle in transgenic mice where it causes only relatively minor splicing changes but no effect on longevity28.…”

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

“…The involvement of autophagy in DM1 was largely deduced from the presence of autophagic vesicles and/or accumulation of autophagic markers in DM1 cells, but usually without dynamic measurement of the autophagic flux (13,14,17,19,36,37,49). In our study, we combined several methods to establish that mild changes in autophagic markers in muscle from HSA LR mice are caused by autophagic flux limitation during the degradation steps.…”

“…Recently, deregulation of cellular processes and signaling pathways important for maintaining proper muscle homeostasis has been reported in DM1. This includes abnormal activation of the ubiquitin-proteasome system and increased autophagic flux, which were both related to muscle atrophy and weakness in DM1 (12)(13)(14). In parallel, perturbation in the PKB/Akt pathway may arise from altered expression of the insulin receptor, which correlates with glucose intolerance in DM1 patients (15).…”

“…In parallel, perturbation in the PKB/Akt pathway may arise from altered expression of the insulin receptor, which correlates with glucose intolerance in DM1 patients (15). Although PKB/Akt deregulation has been reported in Dmpk-deficient mice (16), in DM1 flies (13), and in DM1 human neural stem cells (17), contradictory results have been obtained in human muscle cells (18,19).…”

Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

“…In relation to autophagy, EPO inhibits autophagy through the activation of mTOR (20, 57, 266). Activation of mTOR blocks autophagy by phosphorylating autophagic related genes ( Atg ) and proteins that include Atg13 and ULKs to inhibit the UNC like kinase complex ULK-Atg13-FIP200 (37).…”