SUMMARY Although maternal exercise (ME) becomes increasingly uncommon, the effects of ME on offspring muscle metabolic health remain largely undefined. Maternal mice are subject to daily exercise during pregnancy, which enhances mitochondrial biogenesis during fetal muscle development; this is correlated with higher mitochondrial content and oxidative muscle fibers in offspring muscle and improved endurance capacity. Apelin, an exerkine, is elevated due to ME, and maternal apelin administration mirrors the effect of ME on mitochondrial biogenesis in fetal muscle. Importantly, both ME and apelin induce DNA demethylation of the peroxisome proliferator-activated receptor γ coactivator-1α ( Ppargc1a ) promoter and enhance its expression and mitochondrial biogenesis in fetal muscle. Such changes in DNA methylation were maintained in offspring, with ME offspring muscle expressing higher levels of PGC-1α1/4 isoforms, explaining improved muscle function. In summary, ME enhances DNA demethylation of the Ppargc1a promoter in fetal muscle, which has positive programming effects on the exercise endurance capacity and protects offspring muscle against metabolic dysfunction.

Scope As a natural compound in foods, alpha‐ketoglutarate (aKG) is one of the key metabolites maintaining energy homeostasis. This study examines the beneficial effects of dietary aKG against the development of experimental colitis and further explores the underlying molecular mechanisms. Methods and Results Eight‐week‐old male C57BL/6 mice receive drinking water with or without 1% aKG for 4 weeks. At week 3, colitis is induced by 2.5% dextran sulfate sodium (DSS) for 7 days followed by 7 days recovery. Dietary aKG supplementation decreases DSS‐induced body weight loss, gross bleeding, fecal consistency score, and disease activity index. In agreement, aKG supplementation restores DSS‐associated colon shortening, ameliorated mucosal damage, and macrophage infiltration into colonic tissue, which are associated with suppressed gut inflammation and Wnt signaling, and improved epithelial structure. Consistently, aKG supplementation enhances M1 to M2 macrophage polarization and strengthens intestinal barrier function. Additionally, aKG supplementation elevates colonic aKG levels while decreasing 2‐hydroxyglutarate levels, which increases oxidative instead of glycolytic metabolism. Conclusion aKG supplementation protects against epithelial damage and ameliorates DSS‐induced colitis, which are associated with suppressed inflammation, Wnt signaling pathway, and glycolysis. Intake of foods enriched with aKG or aKG supplementation can be an alternative approach for the prevention or treatment of colitis that are common in Western societies.

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As the prevalence of inflammatory bowel diseases (IBD) rises, the etiology of IBD draws increasing attention. Glucoraphanin (GRP), enriched in cruciferous vegetables, is a precursor of sulforaphane, known to have anti-inflammatory and antioxidative effects. We hypothesized that dietary GRP supplementation can prevent mitochondrial dysfunction and oxidative stress in an acute colitis mouse model induced by dextran sulfate sodium (DSS). Eight-week-old mice were fed a regular rodent diet either supplemented with or without GRP. After 4 weeks of dietary treatments, half of the mice within each dietary group were subjected to 2.5% DSS treatment to induce colitis. Dietary GRP decreased DSS-induced body weight loss, disease activity index, and colon shortening. Glucoraphanin supplementation protected the colonic histological structure, suppressed inflammatory cytokines, interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α), and reduced macrophage infiltration in colonic tissues. Consistently, dietary GRP activated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, and nuclear factor erythroid 2-related factor 2 (NRF2) pathways in the colonic tissues of DSS-treated mice, which was associated with increased mitochondrial DNA and decreased content of the oxidative product 8-hydroxydeoxyguanosine (8-OHDG), a nucleotide oxidative product of DNA. In conclusion, dietary GRP attenuated mitochondrial dysfunction, inflammatory response, and oxidative stress induced by DSS, suggesting that dietary GRP provides a dietary strategy to alleviate IBD symptoms.

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