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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 (RFCSA ) 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 = -0.72, p = 6 × 10-4 with RFCSA on Day 0, P = 3 × 10-4 with RFCSA on Day 7 and r = -0.73, P = 5 × 10-4 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 × 10-4 ) and that GDF-15, interleukin (IL)-8), C-C 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.

SUBMITTER: Kemp PR

PROVIDER: S-EPMC7567140 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Kemp Paul R PR Paul Richard R Hinken Aaron C AC Neil David D Russell Alan A Griffiths Mark J MJ

Journal of cachexia, sarcopenia and muscle 20200716 5

<h4>Background</h4>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.<h4>Methods</h4>To determi ...[more]

PMID: 32677363

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Project description:Over the last 10 years we have significantly reduced hospital mortality from sepsis and critical illness. However, the evidence reveals that over the same period we have tripled the number of patients being sent to rehabilitation settings. Further, given that as many as half of the deaths in the first year following ICU admission occur post ICU discharge, it is unclear how many of these patients ever returned home. For those who do survive, the latest data indicate that 50-70% of ICU "survivors" will suffer cognitive impairment and 60-80% of "survivors" will suffer functional impairment or ICU-acquired weakness (ICU-AW). These observations demand that we as intensive care providers ask the following questions: "Are we creating survivors ... or are we creating victims?" and "Do we accomplish 'Pyrrhic Victories' in the ICU?" Interventions to address ICU-AW must have a renewed focus on optimal nutrition, anabolic/anticatabolic strategies, and in the future employ the personalized muscle and exercise evaluation techniques utilized by elite athletes to optimize performance. Specifically, strategies must include optimal protein delivery (1.2-2.0 g/kg/day), as an athlete would routinely employ. However, as is clear in elite sports performance, optimal nutrition is fundamental but alone is often not enough. We know burn patients can remain catabolic for 2 years post burn; thus, anticatabolic agents (i.e., beta-blockers) and anabolic agents (i.e., oxandrolone) will probably also be essential. In the near future, evaluation techniques such as assessing lean body mass at the bedside using ultrasound to determine nutritional status and ultrasound-measured muscle glycogen as a marker of muscle injury and recovery could be utilized to help find the transition from the acute phase of critical illness to the recovery phase. Finally, exercise physiology testing that evaluates muscle substrate utilization during exercise can be used to diagnose muscle mitochondrial dysfunction and to guide a personalized ideal heart rate, assisting in recovery of muscle mitochondrial function and functional endurance post ICU. In the end, future ICU-AW research must focus on using a combination of modern performance-enhancing nutrition, anticatabolic/anabolic interventions, and muscle/exercise testing so we can begin to create more "survivors" and fewer victims post ICU care.

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

Publications

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

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