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 <i>rb1cc1-</i> and <i>atg14-</i>conditional knockout (cKO) mice by using <i>Ckm/Ckmm2-Cre</i> and compared their phenotypes to those of <i>ulk1 ulk2</i>-conditional double-knockout (cDKO) mice. <i>atg14</i>-cKO mice developed hypertrophic cardiomyopathy, which was associated with abnormal accumulation of autophagic cargoes in the heart and early mortality. Skeletal muscles of both <i>atg14</i>-cKO and <i>rb1cc1</i>-cKO mice showed features of autophagic vacuolar myopathy with ubiquitin⁺ SQSTM1⁺ deposits, but only those of <i>rb1cc1</i>-cKO mice showed TARDBP/TDP-43⁺ pathology and other features of the inclusion body myopathy–like disease we previously described in <i>ulk1 ulk2</i>-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. <b>ABBREVIATIONS</b>:AVM: autophagic vacuolar myopathy; cDKO: conditional double knockout; cKO: conditional knockout; H&amp;E: hematoxylin and eosin; IBM: inclusion body myopathy; mtDNA: mitochondrial DNA; PFA: paraformaldehyde; RNP: ribonucleoprotein; TBST: Tris-buffered saline with 0.2% Triton X-100