FGF21–Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity

Abstract

BACKGROUND: Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms. METHODS: The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective β-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell–derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction. RESULTS: Treadmill exercise markedly induced cardiac expression of β-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of β-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell–derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM. CONCLUSIONS: The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03240978.

Resistance exercise protects mice from protein-induced fat accretion

“…Here, we have not examined the effects of dietary protein and exercise on molecular changes and have not explained how WP inhibits HP-induced gains in adiposity. The hormone FGF21, which is induced by a LP diet, is responsive to exercise in mice and humans (Haghighi et al, 2022; Jin et al, 2022; Li et al, 2022), but we did not observe increased FGF21 in the LP weight trained group, suggesting another mechanism could be at play. As for the improved body composition of HP-fed WP mice, we hypothesize that these interventions may activate beiging in iWAT or BAT.…”

“…In regards to molecular changes, we have not explained how WP inhibits HP-induced gains in adiposity. The hormone FGF21, which is induced by a LP diet, is responsive to exercise in mice and humans (Haghighi et al, 2022; Jin et al, 2022; Li et al, 2022) and we hypothesize that WP in HP-fed mice may activate beiging in iWAT or BAT activity. We have not explored the role of individual amino acids in the response; many athletes and body builders take supplements in the BCAAs, and future work should determine if there is a specific role for these or other dietary amino acids in the metabolic and physiological response to resistance exercise.…”

Exercise-Induced Fibroblast Growth Factor-21: A Systematic Review and Meta-Analysis

“…FGF-21 induced the AMPK/FOXO3/SIRT3 signaling axis in stem-cell-derived cardiomyocytes. This resulted in preventing mitochondrial dysfunction and oxidative stress [ 64 ]. From a new point of view, biological functions were also found to be performed in the vascular unit, and it was reported to reduce the risk of bleeding by inhibiting thrombus formation [ 65 ].…”

Fibroblast growth factor 21 and prognosis of patients with cardiovascular disease: A meta-analysis

“…This paradox may be because of a compensatory response to metabolic stress in patients with CVD. FGF21 resistance may be another underlying mechanism, according to recent findings reporting that stress conditions can decrease FGF21 coreceptor b-Klotho expression in the heart, impair FGF21 signaling, and weaken the protective effect of FGF21 on cardiomyocytes (46). Both underlying mechanism studies and high-level clinical trials are needed to determine this uncertainty to provide potential drug targets.…”