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ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.

ABSTRACT: 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.ABBREVIATIONS:AVM: autophagic vacuolar myopathy; cDKO: conditional double knockout; cKO: conditional knockout; H&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.

SUBMITTER: Li D

PROVIDER: S-EPMC8496527 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.

Li Dongfang D Vogel Peter P Li-Harms Xiujie X Wang Bo B Kundu Mondira M

Autophagy 20210414 9

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 associat ...[more]

PMID: 33794726

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ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.

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ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.

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