Abstract
Introduction: p49/STRAP (SRFBP1) is a serum response factor (SRF) binding protein, which regulates many genes. p49/STRAP has a SRF binding domain and a BUD22 domain (which modulates growth and cell size). In addition, p49/STRAP alters the intracellular NAD/NADH ratio and induces protein deacetylation. Hypothesis: Alteration of NAD/NADH ratio by p49/STRAP might affect acetylation and deacetylation of histone proteins, which may impact the transcription of a number of genes that are involved in energy metabolism and mitochondrial respiration, thereby affecting cardiac function in aging. Methods and Results: p49/STRAP overexpression or knockdown was performed using plasmid or siRNA. Seahorse XF96 Flux Analyzer was used to measure mitochondrial respiration and glycolysis. p49 overexpression caused deacetylation of histone H4 on lysine 16 (H4K16); knockdown of p49/STRAP increased H4K16 acetylation. PPAR gamma (PPARγ) Coactivator-1 (PGC-1) is an important regulator of mitochondrial genes. P49 repressed PGC-1α expression, while P49 siRNA increased the PGC-1α expression. p49/STRAP also repressed mitofusin 1 and 2 genes. Knockdown of p49/STRAP increased the expression of mitofusin 1 and 2 genes. MitoTracker staining revealed that p49/STRAP reduced the mitochondrial membrane potential and the mitochondrial size. Furthermore, p49/STRAP repressed mitochondrial basal respiration, maximal respiration and spare respiration capacity. Conclusion: p49/STRAP caused the deacetylation of histone H4K16 and repressed the expression of multiple genes related to mitochondrial structure and function, including the PGC-1α gene. Repression of PGC-1α could affect PGC-1 transcriptional networks in the cardiac muscles. The age-associated increased cardiac expression of p49/STRAP may contribute to mitochondrial functional decline in the heart during senescence.