Metabolic profiling shows pre‐existing mitochondrial dysfunction contributes to muscle loss in a model of ICU‐acquired weakness

Abstract

Background Surgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting. Methods To determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile 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 (RF CSA) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites 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 = À0.72, p = 6 × 10 À4 with RF CSA on Day 0, P = 3 × 10 À4 with RF CSA on Day 7 and r = À0.73, P = 5 × 10 À4 with 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 cortisol to 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 nucleotides 3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan® showed that pre-surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF-15) (r = 0.79, P = 2 × 10 À4) and that GDF-15, interleukin (IL)-8), CC motif chemokine 23 (CCL-23), and IL-15 receptor subunit alpha (IL-15RA) contributed to metabolic changes in response to surgery. Conclusions We show that pre-existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF-15 and IL-15RA in mitochondrial dysfunction.

Targeted Metabolomic Analysis in Alzheimer’s Disease Plasma and Brain Tissue in Non-Hispanic Whites

“…Another possible reason for neuromuscular degeneration occurring in AD is related to mitochondrial dysfunction [ 70–72 ], promoted by oxidative stress, inflammatory environment, and insulin resistance [ 73 ], which is considered to be related to AD [ 74 ]. We observed elevated acylcarnitines, key elements in mitochondrial beta-oxidation, which accumulate during mitochondrial impairment [ 75 ] and correlate with ICU-acquired muscle loss [ 76 ]. Further, aconitic acid (plasma only) and succinic acid are elevated, suggesting a disturbed mitochondrial tricarboxylic acid (TCA) cycle, possibly due to inefficient succinate dehydrogenase, which is involved in neurodegeneration and lipid accumulation [ 77 ].…”

“…We observed elevated acylcarnitines, key elements in 644 mitochondrial beta-oxidation, which accumulate during mitochondrial impairment [75] and correlate with ICU-acquired muscle loss [76]. Further, aconitic acid (plasma only) and succinic acid are elevated, suggesting a disturbed mitochondrial tricarboxylic acid (TCA) cycle, possibly due to inefficient succinate dehydrogenase, which is involved in neurodegeneration and lipid accumulation [77].…”

Myokines and Heart Failure: Challenging Role in Adverse Cardiac Remodeling, Myopathy, and Clinical Outcomes

“…Although the natural killer cell receptor/IL-15 signaling pathway contributes to progressive inflammatory muscle destruction and myopathy [ 166 ], whether this molecular mechanism is essential for regulation of HF-related myopathy is not fully clear. Thus, muscle-derived IL-15 appears to have important roles in metabolism of both the myocardium and skeletal muscles, and exercise plays a role in the interplay between WAT modification and inflammation, but its value in HF-related myopathy remains to be poorly understood [ 167 , 168 ].…”

Nutritional and Nutrition-Related Biomarkers as Prognostic Factors of Sarcopenia, and Their Role in Disease Progression

“…An increase of the levels of certain types of acylcarnitine, has been found to be associated with dysregulation of fatty acid metabolism [ 60 ]. Dysfunction of metabolic pathways in mitochondria has been reported to contribute to the decrease of muscle mass and loss of muscle strength [ 61 ]. In addition, recent studies reveal that certain types of carnitine in blood, are found in insufficient levels in sarcopenic patients and were significantly correlated with the skeletal muscle index (SMI).…”