Sam68 Exacerbates Pathological Cardiac Hypertrophy by Suppressing Cardiomyocyte Glucose Oxidation
Authors: An Junqing , Han Chaoshan , Jiang Ying , Shi Jiawei , Li Huadong , Wang Chenqi , Huang Jianrong , Xu Shiyue , Dong Nianguo , Qin Gangjian 
Published: February 2025

Background

Impaired energy metabolism in the heart is critical in the development of cardiac hypertrophy and failure. Src-associated in mitosis 68 kDa (Sam68) is a member of the signal transducer and activator of RNA (STAR) protein family, and its role in cardiac energy metabolism is undefined.

Methods

We assessed Sam68 expression in human myopathic and failing hearts. We also generated mice with cardiomyocyte-specific Sam68 deletion or overexpression and subjected them to angiotensin II infusion or transverse aortic constriction (TAC) surgery to induce pathological cardiac hypertrophy. Mechanistic studies were performed using RNA-seq, metabolomics, and immunoprecipitation analyses.

Results

Sam68 expression was significantly elevated in cardiomyocytes of human myopathic and failing hearts. Deletion of Sam68 in adult mouse cardiomyocytes prevented angiotensin II- and TAC-induced cardiac hypertrophy. Conversely, AAV9-mediated overexpression of Sam68 in cardiomyocyte exacerbated cardiac hypertrophy and failure. RNA-seq and metabolomic analyses showed that Sam68 deficiency led to a marked downregulation of pyruvate dehydrogenase kinase 4 (PDK4), which was associated with enhanced cardiac glucose oxidation and oxidative phosphorylation. Mechanistically, Sam68 directly interacts with STAT3, promoting its phosphorylation and nuclear translocation via Src signaling, thereby enhancing PDK4 transcription. Pharmacological inhibition of the Sam68-Src interaction using a specific peptidomimetic molecule mitigated pathological cardiac hypertrophy by attenuating STAT3 phosphorylation and restoring glucose oxidation. Additionally, the Sam68/STAT3/PDK4 signaling axis was significantly unregulated in patients with heart failure.

Conclusions

Our findings reveal a novel role of Sam68 in regulating cardiac glucose oxidation, highlighting the potential therapeutic targeting of Sam68 for managing cardiac hypertrophy and heart failure.

Clinical Perspective What Is New?

Sam68 (Src-associated-in-mitosis-of-68kDa) expression is upregulated in human failing hearts and in mouse models of cardiac hypertrophy and heart failure.

Deletion of Sam68 in cardiomyocytes mitigates pressure overload-induced cardiac hypertrophy and dysfunction, while overexpression of Sam68 exacerbates these conditions.

Sam68 exacerbates pressure overload-induced cardiac hypertrophy and dysfunction by binding to STAT3, increasing its phosphorylation and nuclear translocation, which ultimately leads to the upregulation of PDK4 and impairment of glucose oxidation.

What Are the Clinical Implications?

Upregulation of the Sam68/STAT3/PDK4 signaling axis in cardiomyocytes is associated with the development of cardiac hypertrophy and heart failure.

Pharmacological inhibition of Sam68 has the potential to improve cardiac energy metabolism, offering new therapeutic options for treating cardiac hypertrophy.

By modulating the Sam68/STAT3/PDK4 axis, it may be possible to enhance glucose oxidation and mitigate the progression of heart failure.