Exercise-Generated β-Aminoisobutyric Acid (BAIBA) Reduces Cardiomyocyte Metabolic Stress and Apoptosis Caused by Mitochondrial Dysfunction Through the miR-208b/AMPK Pathway

Abstract

ObjectiveTo explore the cardioprotective effects of exercise-derived β-aminoisobutyric (BAIBA) on cardiomyocyte apoptosis and energy metabolism in a rat model of heart failure (HF).MethodsIn male Sprague-Dawley rats (8-week-old), myocardial infarction (MI) was used to induce HF by ligating the left anterior descending branch of the coronary artery. In the Sham group, the coronary artery was threaded but not ligated. After HF development, Sham and HF rats were exercised 60 min daily, 5 days/week on a treadmill for 8 weeks (50–60% maximal intensity) and exercise-induced cardiac remodeling after MI were assessed using echocardiography, hematoxylin and eosin (H&E), Masson's Trichrome, and TUNEL staining for the detection of apoptosis-associated factors in cardiac tissue. High-throughput sequencing and mass spectrometry were used to measure BAIBA production and to explore its cardioprotective effects and molecular actions. To further characterize the cardioprotective effects of BAIBA, an in vitro model of apoptosis was generated by applying H2O2 to H9C2 cells to induce mitochondrial dysfunction. In addition, cells were transfected with either a miR-208b analog or a miR-208b inhibitor. Apoptosis-related proteins were detected by Western Blotting (WB). ATP production was also assessed by luminometry. After administration of BAIBA and Compound C, the expression of proteins related to apoptosis, mitochondrial function, lipid uptake, and β-oxidative were determined. Changes in the levels of reactive oxygen species (ROS) were assessed by fluorescence microscopy. In addition, alterations in membrane potential (δψm) were obtained by confocal microscopy.ResultsRats with HF after MI are accompanied by mitochondrial dysfunction, metabolic stress and apoptosis. Reduced expression of apoptosis-related proteins was observed, together with increased ATP production and reduced mitochondrial dysfunction in the exercised compared with the Sham (non-exercised) HF group. Importantly, exercise increased the production of BAIBA, irrespective of the presence of HF. To assess whether BAIBA had similar effects to exercise in ameliorating HF-induced adverse cardiac remodeling, rats were treated with 75 mg/kg/ day of BAIBA and we found BAIBA had a similar cardioprotective effect. Transcriptomic analyses found that the expression of miR-208b was increased after BAIBA administration, and subsequent transfection with an miR-208b analog ameliorated both the expression of apoptosis-related proteins and energy metabolism in H2O2-treated H9C2 cells. In combining transcriptomic with metabolomic analyses, we identified AMPK as a downstream target for BAIBA in attenuating metabolic stress in HF. Further cell experiments confirmed that BAIBA increased AMPK phosphorylation and had a cardioprotective effect on downstream fatty acid uptake, oxidative efficiency, and mitochondrial function, which was prevented by the AMPK inhibitor Compound C.ConclusionExercise-generated BAIBA can reduce cardiomyocyte metabolic stress and apoptosis induced by mitochondrial dysfunction through the miR-208b/AMPK pathway.

Melphalan induced germ cell toxicity and dose‐dependent effects of β‐aminoisobutyric acid in experimental rat model: Role of oxidative stress, inflammation and apoptosis

“…BAIBA has also been reported as a potent antioxidant and antiapoptotic agent in in-vitro as well as invivo studies. [59,60] Besides this, melphalan also decreased the expression of β-tubulin in the sperm tail. Since, β-tubulin is the key cytoskeletal protein responsible for the motility of sperm; a decrease in its expression might be responsible for the perturbation of sperm motility.…”

“…[61] An earlier study also reported that BAIBA restored the H 2 O 2 -induced MMP alterations and improved the mitochondrial biogenesis as well as functions in H9C2 cardiomyocytes mediated through miR-208b/AMPK pathway. [60] Further, the ultrastructural oxidative stress in the osteocytes, PC12 cells in-vitro as well as in diabetes-induced hepatic toxicity in vivo. [16,59,62] mice.…”

“…BAIBA has also been reported as a potent antioxidant and antiapoptotic agent in in‐vitro as well as in‐vivo studies. [ 59,60 ]…”

The L-enantiomer of β- aminobutyric acid (L-BAIBA) as a potential marker of bone mineral density, body mass index, while D-BAIBA of physical performance and age.

“…We showed that murine contracted muscle produces the L but not the Denantiomer and that L-BAIBA has a protective effect on bone (6). A recent study of heart failure in rats showed that L-BAIBA produced during treadmill exercise has a protective effect on cardiac muscle cells (21).…”

“…To be included in the current analyses, individuals needed to be 20-85 years of age, self-reported white and non-Hispanic, and without a self-reported major chronic disease. Individuals within each sex and each 15 year age group (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)35-50, 50-65, and 65 + yrs) were ranked for their performance on the FIT Core's hand grip strength test and test of the number of chair stands completed in 30 seconds (Fig. 1A).…”