(685.6) Targeting p21-highly-expressing Senescent Cells Enhances Skeletal Muscle Function through Mitochondrial Function and Reactive Oxygen Species

Poster Board Number: A530

Sung Gi Noh (University of Connecticut), Ahram Ahn (University of Connecticut), Lichao Wang (University of Connecticut Health, University of Connecticut Health), Ming Xu (University of Connecticut Health, University of Connecticut Health), Oh Sung Kwon (University of Connecticut, University of Connecticut Health)

Background: The accumulation of senescent cells is a hallmark of aging in the skeletal muscle which causes reactive oxygen species (ROS) and mitochondrial dysfunction. p21 is one of the major regulators and most recognized cellular markers for senescent cells. Recent evidence demonstrated that clearance of p21 high cells enhances muscle function including grip strength, hanging endurance, and maximal walking speed in mice. However, it is still unclear how the muscle performance enhances through the clearance of p21 high cells. One of the potential mechanisms is mitochondrial function and/or mitochondria-derived ROS. Therefore, this study investigated the linkage between mitochondria and p21 high cells in aging or high fat diet-induced muscle dysfunction.

Methods: Five p21-Cre/+; +/+ (P) and p21-Cre/+; DTA/+ (PD) obese mice fed by high fat diet were administrated with tamoxifen for twice. Five P lean mice fed by normal chow were adopted as normal control. We previously demonstrated that p21high cells accumulate in obese P mice, and can be eliminated in obese PD mice by tamoxifen treatment. Mitochondrial respiration was measured, by high-resolution respirometry, in permeabilized muscle fibers from the soleus muscle. Mitochondria-derive ROS production was determined using Amplex Red assays. One-way ANOVAs with Bonferroni post-hoc were used to determine differences between groups (P lt; 0.05).

Results: Reductions in complex I + II state 3 respiration were observed in p21-Cre mice with high fat diet but the clearance of p21 high cells using tamoxifen enhanced complex I + II state 3 respiration (Lean P: 35.2 ± 3.13 pmol·s-1·mg-1; Obese P: 17.45 ± 2.85 pmol·s-1·mg-1; Obese PD: 30.04 ± 3.19 pmol·s-1·mg-1; P lt; 0.05). State 4 respiration did not differ between groups (P gt; 0.05). Respiratory Control Ratio (RCR), defined as respiration in state 3 divided by respiration in state 4, significantly decreased in high fat diet group but clearing p21 high cells restored respiratory function (Lean P: 4.20 ± 1.18; Obese P: 2.21 ± 1.11; Obese PD: 3.85 ± 1.60; Plt;0.05). Also, high fat diet increased mitochondrial ROS production, but tamoxifen treatment attenuated ROS production (Lean P: 10.16 ± 0.41 pmol·s-1·mg-1; Obese P: 26.83 ± 0.54 pmol·s-1·mg-1; Obese PD: 12.23 ± 0.54 pmol·s-1·mg-1; Plt;0.05).

Conclusion: These results demonstrated that p21high cells may play a causal role in mitochondrial dysfunction and ROS emission in the skeletal muscle with obesity and other chronic diseases. Therefore, targeting p21high cells may enhance muscle performance through decreasing mitochondria-derived ROS and enhancing mitochondrial function.