DOI: 10.2337/db23-304-or ISSN: 0012-1797

304-OR: Reduced VDAC1 Limits ROS Release to Restrain Oxidative Damage in Muscle of 3-Year-Old Nonhuman Primates with Early-Life Exposure to Maternal Western Diet or Obesity

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

Offspring from obese pregnancies have an elevated risk for childhood obesity and chronic metabolic diseases. Using a Japanese macaque model of early-life maternal Western-style diet (mWD) exposure, we previously observed decreased oxidative capacity and elevated markers of mitophagy in skeletal muscle of 3-yr-old offspring. We also found substantial reductions in VDAC1 content, the loss of which significantly correlated with decreased whole-muscle lipid peroxidation in mWD offspring. For this study, we isolated the impact of mWD from mWD-induced obesity by studying offspring from both lean (Ln, body fat <25%) or obese (Ob, body fat >30%) dams fed a WD or lean dams fed a control diet (CD) prior to and throughout pregnancy and lactation. All offspring were weaned to CD and offspring gastrocnemius was collected at 40 months of age. This design created three offspring groups: LnCD, LnWD and ObWD. In offspring muscle, VDAC1, but not VDAC2, was significantly decreased in LnWD, and was further reduced in ObWD. In contrast to whole-tissue, lipid peroxidation in a mitochondrial-enriched fraction was increased in offspring muscle from LnWD and ObWD groups. Markers of mtDNA damage were also elevated in ObWD muscle. Lastly, Sirt3 abundance, a master regulator of mitochondrial antioxidant defense, was reduced in muscle from both LnWD and ObWD. These data suggest that ROS are retained within the mitochondrial compartment due, in part, to VDAC1 suppression, resulting in an overall reduction in cellular oxidant burden. These findings elucidate a long-term adaptation to early life stress caused by mWD and obesity which limits cellular damage at the expense of mitochondrial function.


K.T.Greyslak: None. C.E.Mccurdy: None.


National Institutes of Health (R24DK090964); Eugene Evonuk Memorial Graduate Fellowship

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