SIRT3 and Myocardial fibrosis: Consistent with this, AP-1 transcriptional activity was increased after SIRT3 deletion (Fig. 2f), and this was correlated with the enhanced expression of the AP-1 target gene ATF4 (activating transcription factor 4; Supplementary Fig. S1e), a profibrotic transcription factor that controls the synthesis of type I collagen and other fibrosis-related proteins.19 In fact, SIRT3 knockout mice spontaneously developed myocardial fibrosis, since the collagen content in the heart was higher in knockout mice than in WT mice (Fig. 2g).