(605.29) MYTHO: A novel regulator of autophagy and skeletal muscle health

Poster Board Number: E509

Jean-Philippe Leduc-Gaudet (Venetian Institute of Molecular Medicine (VIMM) and Department of Biomedical Science, University of Padova, Venetian Institute of Molecular Medicine (VIMM) and Department of Biomedical Science, University of Padova, Venetian Institute of Molecular Medicine (VIMM) and Department of Biomedical Science, University of Padova, Venetian Institute of Molecular Medicine (VIMM) and Department of Biomedical Science, University of Padova), Anaïs Franco-Romero (Venetian Institute of Molecular Medicine (VIMM) and Department of Biomedical Science, University of Padova), Felipe Broering (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Alaa Moamer (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Marina Cefis (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program, Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Tomer Chaffer (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Maude Dulac (Faculté des Sciences), Vincent Marcangeli (Faculté des Sciences), Sami Sedraoui (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Anwar Shams (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Dominique Mayaki (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Laurent Huck (Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program), Basil Petrof (McGill University Health Centre, McGill University Health Centre), Hanns Lochmuller (Childrens Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa), Marco Sandri (Venetian Institute of Molecular Medicine (VIMM) and Department of Biomedical Science, University of Padova), Sabah Hussain (McGill University Health Centre, McGill University Health Centre), Gilles Gouspillou (Faculté des Sciences, Faculté des Sciences)

Rationale: The loss of skeletal muscle function can have dramatic health consequence. Skeletal muscle dysfunction are found in a wide range of clinical conditions, including cancer cachexia, starvation, sepsis, and aging. Autophagy is an essential catabolic process that remove damaged cytosolic components. Accumulating evidence indicates that insufficient or excessive autophagy can contribute to the development of skeletal muscle atrophy. We recently identified a novel FoxO-dependent gene, which we named MYTHO, with the potential to regulate autophagy in skeletal muscles. However, to date, the roles that MYTHO plays in skeletal muscles remain unknown. In this study, we evaluated the functional importance of MYTHO in skeletal muscle structure and function.

Methods: To study the functional importance of MYTHO in skeletal muscle mass and function, we used a combination of genetic strategies in mice to delete or overexpress MYTHO.

Results: MYTHO expression is induced in various muscle wasting conditions, including starvation, denervation, cancer cachexia, and sepsis. Using different genetics approaches, we confirmed that MYTHO is an important regulator of autophagy in skeletal muscle. Importantly, we also found that MYTHO knockdown in skeletal muscles caused various myopathic features, including muscle weakness, accumulation of tubular aggregates, a shift in myofiber type composition and nuclei mispositioning in myofibers. Using animals with muscle specific Atg7 deletion (a model of autophagy inactivation), we demonstrated that the pathological features associated with MYTHO knockdown are independent of its role in regulating autophagy.

Conclusion: We conclude that MYTHO is a central player in regulating skeletal muscle mass and integrity.

This study is funded by CIHR grants. GG is supported by a Chercheur Boursier Junior 2 salary award from the FRQS. JPLG is supported by a FRQS postdoctoral fellowship.