title: Reactivation of autophagy ameliorates LMNA cardiomyopathy.
abstract: Mutations in the LMNA gene, which encodes lamin A and C (lamin A/C), cause a diverse spectrum of tissue-selective diseases termed laminopathies. The most prevalent form affects striated muscles as dilated cardiomyopathy with variable skeletal muscle involvement, which includes autosomal Emery-Dreifuss muscular dystrophy. Mechanisms underlying the disease pathogenesis are beginning to be understood and they point toward defects in cell signaling. We therefore assessed putative signaling defects in a mouse model carrying a point mutation in Lmna (Lmna (H222P/H222P) ) that faithfully recapitulates human Emery-Dreifuss muscular dystrophy. We found that AKT-mechanistic target of rapamycin (MTOR) signaling was hyperactivated in hearts of Lmna (H222P/H222P)  mice and that reducing MTOR activity by pharmacological intervention ameliorated cardiomyopathy. Given the central role of MTOR in regulating autophagy, we assessed fasting-induced autophagic responses and found that they were impaired in hearts of these mice. Moreover, the improved heart function associated with pharmacological blockade of MTOR was correlated with enhanced autophagy. These findings demonstrated that signaling defects that impair autophagy underlie pathogenesis of dilated cardiomyopathy arising from LMNA mutation.
authors.affiliation: Department of Medicine and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Choi
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008955:Models, Cardiovascular; D017354:Point Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D034904:Lamin Type A; C576142:Lmna protein, mouse; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases