THE EFFECT OF OBESITY ON CELL CYCLE REGULATION IN SKELETAL MUSCLE DURING REGENERATION

Lemuel A. Brown, Jillian F. Patton, Alyssa M. Papineau, Tyrone A. Washington; Exercise Muscle Biology Laboratory and Human Performance Lab, University of Arkansas, Fayetteville, AR Obesity is associated with impairments in muscle function which is an essential for every day physical activity. Optimal skeletal muscle regeneration requires the coordinated regulation of inflammation, extracellular matrix remodeling, and myofiber growth. Furthermore, myofiber growth is dependent on satellite cell proliferation and differentiation to repair damaged skeletal muscle. Yet, it is still unclear how obesity alters cell cycle regulation during skeletal muscle regeneration. PURPOSE: Determine how obesity alters cellular signaling related to cell cycle regulation during skeletal muscle regeneration in damaged tibialis anterior (TA) muscle. METHODS: Twenty male C57/BL6 mice (12 weeks old) were randomly assigned to either a high fat diet (HFD) (60% fat) or a lean diet (10% fat). Bupivacaine was injected into the TA of the injured group (n = 4-6), and phosphate buffered saline (PBS) was injected into the TA of the uninjured group (n= 4-6) for each diet. Three days post-injection the TA was excised. Gene expression and protein levels inflammatory signaling markers, protein synthesis markers, and cell cycle regulators were determined. RESULTS: The mice on the HFD had 20% more body fat than the lean mice (lean = 24.0% ± 8.8, HFD = 44.7% ± 10.9, p \u3c .05). There was a significant difference in TA muscle mass to bodyweight ratio in lean (1.8 ± 0.13 mg/g vs. 1.6 ± 0.10 mg/g, p \u3c 0.05) and a trend for a decrease in HFD mice (1.5 ± 0.24 mg/g vs. 1.3 ± 0.13 mg/g, p = 0.07) 3 days post-bupivacaine injection. Three days after bupivacaine injection protein levels of protein synthesis marker, p-AKT, increased 3-fold in both lean and HFD mice (p \u3c .05). Protein levels of p-STAT3, a marker for inflammation, increased 3-fold in the lean mice (p \u3c .05) and 2-fold in HFD mice (p \u3c .05). Injured lean mice had a 20-fold increase in cyclin D1 gene expression (p \u3c .05) 3 days post-bupivacaine injection. However, HFD mice only had a 4.5-fold increase (p \u3c .05) in cyclin D1 gene expression 3 days post-bupivacaine injection. CONCLUSION: In conclusion, cell cycle regulation appears to be dysregulated in obese mice. This work was supported by a grant from the American Biosciences Institut