Maternal obesity leads to muscle dysfunction via <i>H19</i>-mediated programming of insulin-

<p dir="ltr">42% of American women of childbearing age are obese, impacting offspring muscle and metabolism. The IGF2 pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. <i>H19</i>, a long non-coding RNA, is reciprocally regulated with <i>Igf2,</i> which has multiple promoters (P0-P3). <i>H19</i> interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 depositing H3K27me3. We found that MO increased fetal <i>H19</i> expression and investigated how <i>H19</i> epigenetically regulates <i>Igf2</i> in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and</p><p dir="ltr">3-month-old offspring were used for assessing muscle function and metabolism. MO increased <i>H19 </i>expression, enhancing <i>H19</i>-EZH2 interaction and H3K27me3-mediated repression of <i>Igf2</i> in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific <i>H19</i> overexpression were also used. Weaning offspring with <i>H19</i> overexpression showed reduced muscle mass, strength, endurance, and altered structure. Primary myogenic cells from <i>H19</i> overexpressing neonates showed suppressed <i>Igf2</i> expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, <i>H19</i> overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the <i>Igf2</i> P3 promoter. These data show that MO impairs muscle development by disrupting IGF2</p><p dir="ltr">signaling through <i>H19</i>-EZH2 interaction, affecting offspring muscle function.</p>