Abstract Background Sarcopenia, or skeletal muscle loss, impacts up to 40% of COPD patients and is a major cause of morbidity and mortality. Nocturnal hypoxemia is common in COPD and associated with upregulation of skeletal muscle HIF1α associated with a sarcopenic phenotype in vitro and in vivo. We hypothesized that muscle-specific deletion of HIF1α restores skeletal muscle function in murine models of COPD, including elastase-induced emphysema and nocturnal hypoxemia. Design HIF1α loxP transgenic mice with a C57BL/6 background (Jackson Laboratory) age 11 wks underwent tamoxifen-induced Cre-mediated muscle specific deletion (msd) of HIF1α compared to flox/flox (fl/fl) controls. Mouse models of COPD included porcine pancreatic elastase-induced emphysema or models of nocturnal hypoxemia (12 hrs of 10% oxygen /12 hrs of 21% oxygen x 3 weeks). Skeletal muscle tissue was harvested and weighed after euthanasia. Muscle contractile force was determined ex vivo from the quadriceps and diaphragm using a Radnoti muscle bath system. Muscle mitochondrial function was determined from the gastrocnemius muscle using high-sensitivity respirometry (Oroboros). Results Mice with muscle specific deletion (msd) of HIF1α demonstrated increased mitochondrial function in both models of COPD (i.e. elastase-induced emphysema and nocturnal hypoxemia) as compared to littermate HIF1αfl/fl controls. Maximum respiratory capacity of mitochondria was restored in both the HIF1αmsd elastase and in the HIF1αmsd nocturnal hypoxemia model as compared to HIF1αfl/fl controls. Contractile force of the quadriceps and diaphragm was consistently higher when quantified from 1 to 200 Hz (180 mA) in mice with elastase-induced emphysema and muscle specific deletion of HIF1α as compared to HIF1αfl/fl controls. Conclusion Muscle-specific deletion of HIF1α restored mitochondrial function and contractile force in the quadriceps and diaphragm of murine COPD models. Our data lay the foundation for future studies to determine the mechanism whereby HIF1α contributes to sarcopenia in models of COPD. This abstract is funded by: K08 HL16834801A1
Attaway et al. (Fri,) studied this question.