Activation of autophagy ameliorates cardiomyopathy in Mybpc3-targeted knock-in mice

Background. Alterations in autophagy have beenreported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vicisyndrome or LEOPARD syndrome, but not in HCM caused by mutations in genesencoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cardiac myosin-bindingprotein C, is the most frequently mutated HCM gene.

Methods andResults.We evaluated autophagy in HCM patients carrying MYBPC3 mutations and in a Mybpc3-targetedknock-in (KI) HCM mouse model, as well as the effect of autophagy modulators onthe development of cardiomyopathy in KI mice. Microtubule-associatedprotein 1 light chain 3 (LC3)-II protein levels were higher inHCM septal myectomies than in non-failing control hearts and in 60-week-old KIthan wild-type (WT) mouse hearts. In contrast to WT, autophagic flux wasblunted and associated with accumulation of residual bodies and glycogen in heartsof 60-week-old KI mice. We found that Akt-mTORC1 signaling was increased, and treatmentwith 2.24 mg/kgxd rapamycin or 40% caloric restriction for 9 weeks partiallyrescued cardiomyopathy or heart failure and restored autophagic flux in KImice.

Conclusions. Altogether, we found that i) autophagyis altered in HCM patients with MYBPC3mutations, ii) autophagy is impaired in Mybpc3-targetedKI mice and iii) activation of autophagy ameliorated the cardiac disease phenotypein this mouse model. We propose that activation of autophagy might be anattractive option alone or in combination with another therapy to rescue HCM causedby MYBPC3 mutations.