Abstract
Obesity leads to a loss of muscle mass and impaired muscle regeneration. In obese individuals, pathologically elevated levels of prolyl hydroxylase domain enzyme 2 (PHD2) limit skeletal muscle hypoxia-inducible factor-1 alpha and vascular endothelial growth factor (VEGF) expression. Loss of local VEGF may further impair skeletal muscle regeneration. We hypothesized that PHD2 inhibition would restore vigorous muscle regeneration in a murine model of obesity. Adult (22-week-old) male mice were fed either a high-fat diet (HFD), with 60% of calories derived from fat, or a regular diet (RD), with 10% of calories derived from fat, for 16 weeks. On day 5 following cryoinjury to the tibialis anterior muscle, newly regenerated muscle fiber cross-sectional areas were significantly smaller in mice fed an HFD as compared to RD, indicating an impaired regenerative response. Cryoinjured gastrocnemius muscles of HFD mice also showed elevated PHD2 levels (twofold higher) and reduced VEGF levels (twofold lower) as compared to RD. Dimethyloxalylglycine, a cell permeable competitive inhibitor of PHD2, restored VEGF levels and significantly improved regenerating myofiber size in cryoinjured mice fed an HFD. We conclude that pathologically increased PHD2 in the obese state drives impairments in muscle regeneration, in part by blunting VEGF production. Inhibition of PHD2 over activity in the obese state normalizes VEGF levels and restores muscle regenerative potential.
Highlights
Skeletal muscle maintenance and recovery from injury rely on robust endogenous repair mechanisms, which become impaired with obesity
Regenerating fibers were detected in both groups at day 5 after injury, fiber CSA was significantly smaller in the high-fat diet (HFD) group as compared to regular diet (RD) group (643 ± 183 vs. 1,092 ± 246 μm2, p < 0.01, n = 5 per group, Figures 1A–D)
Our study demonstrates that prolyl hydroxylase domain enzyme 2 (PHD2) is increased in skeletal muscle following injury in obese mice and is correlated with decreased HIF-1α and vascular endothelial growth factor (VEGF) expression
Summary
Skeletal muscle maintenance and recovery from injury rely on robust endogenous repair mechanisms, which become impaired with obesity. Mice with decreased PHD1 or PHD3 activity exhibit protection against hind limb ischemia and preservation of muscle mass following ischemic insult [21, 25,26,27] This PHD2/ HIF-1α/VEGF pathway has yet to be assessed in the context of induced skeletal muscle injury and repair. To determine the in vivo therapeutic efficacy of PHD2 inhibition in promoting skeletal muscle regeneration, mice continuously fed either an RD or an HFD were injected intraperitoneal (IP) with a 160 mg/kg dose of dimethyloxalylglycine (DMOG) (Sigma-Aldrich, St. Louis, MO, USA) prepared in saline vehicle (0.9% sodium chloride) for 5 days, starting 1 day prior to cryoinjury.
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