Restoration of autophagy as a new strategy for the treatment of congenital muscular dystrophies

Prof. Markus A. Rüegg, Biozentrum, University of Basel


Muscular dystrophies are severe and rare genetic diseases that affect motor function, have a strong impact on the quality of life and often lead to early death. Although the genes mutated in muscular dystrophies have very different cellular localizations, from the extracellular matrix to the nucleus, there are many commonalities between the different subtypes. For example, all muscular dystrophies are characterized by muscle wasting (i.e. loss of muscle mass) and they often show strong alterations in protein degradation pathways. One of those catabolic pathways is macroautophagy (herein referred to as autophagy) that mediates degradation of proteins and organelles in lysosomes and contributes to the maintenance of cellular energy balance. In the proposed research, we aim to study the role of autophagy in two different types of congenital muscular dystrophies.

During our studies on the role of the mammalian target of rapamycin (mTOR) in skeletal muscle, we recently discovered that the multiprotein complex mTORC1 is the key regulator of autophagy in skeletal muscle. In particular, we showed that sustained activation of mTORC1 inhibits the induction of autophagy and causes a severe, late-onset myopathy in mice (Castets et al., 2012). Importantly, inhibition of mTORC1 by the immunosuppressant drug rapamycin normalized autophagy and reversed most, if not all symptoms of the myopathy. Here we now propose to study the signaling events that cause the blockage of autophagy by activated mTORC1 at the transcriptional and phosphoproteome level. In addition, we will investigate the molecular changes induced by rapamycin treatment to specifically identify the pathways affected directly by the sustained activation of mTORC1. These experiments will use state-of-the-art technologies of deep sequencing and label-free mass spectrometry and will be performed in close collaboration with the laboratories of Prof. M. Zavolan (Biozentrum, University of Basel) and Dr. P. Jenö (Proteomic Core Facility; Biozentrum, University of Basel), respectively. We will then study whether any of the identified candidate genes are deregulated in the two mouse models of congenital muscular dystrophies, where autophagy is deregulated and has been suggested to contribute to the disease progression. Finally, we will use in vitro and in vivo perturbation experiments to investigate whether targeting of particular candidate genes will normalize autophagy flux and ameliorate the disease in these dystrophic mouse models.  

In summary, our studies are designed to unravel novel mechanisms important for autophagy that contribute to the disease in congenital muscular dystrophies. The discovery of these mechanisms is thus likely to give insights into new potential treatment options for such devastating, orphan diseases.