ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis

Defects in macroautophagy/autophagy are implicated in the pathogenesis of neuromuscular and heart diseases. To precisely define the roles of autophagy-related genes in skeletal and cardiac muscles, we generated muscle-specific rb1cc1- and atg14-conditional knockout (cKO) mice by using Ckm/Ckmm2-Cre and compared their phenotypes to those of ulk1 ulk2-conditional double-knockout (cDKO) mice. atg14-cKO mice developed hypertrophic cardiomyopathy, which was associated with abnormal accumulation of autophagic cargoes in the heart and early mortality. Skeletal muscles of both atg14-cKO and rb1cc1-cKO mice showed features of autophagic vacuolar myopathy with ubiquitin(+) SQSTM1(+) deposits, but only those of rb1cc1-cKO mice showed TARDBP/TDP-43(+) pathology and other features of the inclusion body myopathy-like disease we previously described in ulk1 ulk2-cDKO mice. Herein, we highlight tissue-specific differences between skeletal and cardiac muscles in their reliance on core autophagy proteins and unique roles for ULK1-ULK2 and RB1CC1 among these proteins in the development of TARDBP(+) pathology.

Automated summary

Defects in macroautophagy/autophagy are implicated in the pathogenesis of neuromuscular and heart diseases. The study generated muscle-specific rb1cc1- and atg14-conditional knockout (cKO) mice and found that atg14-cKO mice developed hypertrophic cardiomyopathy, while rb1cc1-cKO mice showed features of autophagic vacuolar myopathy. Tissue-specific differences between skeletal and cardiac muscles in their reliance on core autophagy proteins and unique roles for ULK1-ULK2 and RB1CC1 were highlighted in the development of TARDBP(+) pathology.