S913 phosphorylation of Ulk1 protects the heart from aging through inhibition of cardiac senescence

We have previously shown that prevention of GSK-3β inactivation with GSK-3β (S9A) stimulates autophagy through phosphorylation of Ulk1 at Ser913. In the current study, we investigated whether cardiac aging is accelerated in Ulk1S913A knock-in mice and whether cardiomyocyte senescence plays an important role in the development of aging cardiomyopathy in these mice.

In systemic heterozygous Ulk1S913A knock-in mice (shS913A), cardiac dysfunction (evidenced by lower ejection fraction and fractional shortening, lower dP/dtmaximum, higher end-diastolic pressure, and higher dP/dtminimum) and fibrosis, along with increased cardiomyocyte senescence (increased P16, P21, IL6, γH2AX, and P53), were observed at 18 months old. RNA-seq analysis showed that numerous genes are differentially expressed in shS913A and littermate wild type (WT) hearts, including those involved in glucose metabolism, cardiac fibrosis, and cellular senescence. The glycolytic activity was higher in adult mouse cardiomyocytes isolated from shS913A than in those from littermate WT mice. In cultured neonatal rat ventricular cardiomyocytes, overexpression of Ulk1S912A induced cellular senescence. Heterozygous cardiac-specific Ulk1S913A knock-in mice (chS913A) developed cardiac dysfunction, hypertrophy, fibrosis, and senescence at 7 months old. ABT-263 treatment (senolysis) attenuated the cardiac dysfunction, hypertrophy, and fibrosis while decreasing the number of γH2AX-positive cardiomyocytes.

The chS913A mice exhibit premature cardiac aging, which is mediated through stimulation of cardiomyocyte senescence. The results support the role of the GSK-3β-Ulk1-autophagy pathway in the heart during aging. Thus, these mice could be useful in studying cardiac aging and senescence.