(952.8) Mitochondrial Uncoupling Decreases Sarcopenic Obesity By Activation of Skeletal Muscle Mitochondrial Quality Control and Attenuated ER Stress

Poster Board Number: E547

Wagner Dantas (Pennington Biomedical Research Center), Elizabeth Zunica (Pennington Biomedical Research Center), Elizabeth Heintz (Pennington Biomedical Research Center), Charles Hoppel (Pennington Biomedical Research Center), Christopher Axelrod (Pennington Biomedical Research Center), John Kirwan (Pennington Biomedical Research Center)

Background: Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified an orally available mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 that selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.

Methods: 80-week-old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body composition, muscle function, energy expenditure, and locomotor activity were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signaling, and mitochondrial structure and function.

Results: BAM15 decreased body weight (~25% reduction, Plt;0.001) which was attributable to increased energy expenditure (~20% increment, Plt;0.001). BAM15 increased muscle mass (~13% increment, Plt;0.001), strength (~37% increment, Plt;0.0001), and locomotor activity (~25% increment, Plt;0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (IL-6 and gp130, both Plt;0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis and reduced inflammation. Specifically, BAM15 activated mitochondrial quality control through AMPK (PINK1-ubiquitin binding and LC3II, Plt;0.01), increased electron transport chain activity (citrate synthase and complex II activity, all Plt;0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, Plt;0.0001) while limiting ER stress (decreased PERK signaling, Plt;0.0001), apoptotic signaling (decreased cytochrome C release and Caspase-3/9 activation, all Plt;0.001), and muscle protein degradation (decreased 14-kDa actin fragment insoluble/soluble ratio, Plt;0.001).

Conclusions: Mitochondrial uncoupling agents such as BAM15 may mitigate age-related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity through activation of mitochondrial quality control and attenuation of ER stress.

NIH funded (R01 DK108089)





Figure 1. Mitochondrial uncoupling preserves skeletal muscle mass and function in aged mice.; Figure 2. Mitochondrial uncoupling enhances muscle mitochondrial biogenesis, respiratory activity, and quality control/network surveillance in aged mice.