Background:Surgery can lead to significant muscle loss,which increasesrecovery time and associateswith increased mortality. Muscle lossis not uniform,with some patients losing significant muscle mass and others losing relatively little, andis likely to be accompanied by marked changes in circulating metabolitesand proteins. Determining these changes may help understand the variability and identify novel therapeutic approachesor markers of muscle wasting.Methods:To determine the association between muscle loss and circulating metabolites we studied 20 male patients (median age,70.5, inter-quartile range,62.5-75)undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3 and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SOMAlogic). Results:Ten patients lost more than 10% of the cross-sectional area of the rectus femoris (RFCSA) and were defined as wasting. Metabolomic analysisshowed 557 circulatingmetabolites were altered following surgery (q<0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q<0.05).Weighted genome co-expression network analysis,identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function(r=-0.72, p=6x10-4with RFCSAon day 0, p=3x10-4with RFCSAon day 7 and r=-0.73, p=5x10-4with hand-grip strength on day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisolto the same extent in wasting and non-wasting patients but the cortisol:cortisone ratio was higher in the wasting patients (day 3 p=0.043 and day 7 p=0.016).Wasting patients also showed a greater increase in circulating nucleotides3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscanÒshowed that pre-surgicalmitochondrial dysfunction was associated with GDF-15 (r=0.79, p=2 x 10-4)and thatGDF-15, IL-8, CCL-23 and IL-15RA contributed to metabolic changes in response to surgery. Conclusions:Weshow that pre-existing mitochondrial dysfunction andreduced cortisol inactivationcontribute to muscle loss following surgery.The data also implicate GDF-15 and IL-15RA in mitochondrial dysfunction.