Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

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Abstract

Objectives:

Acute muscle wasting in the critically ill is common and causes significant morbidity. In a novel human model of acute muscle wasting following cardiac surgery, known or potential circulating modulators of muscle mass—insulin-like growth factor-1, myostatin, and growth and differentiation factor-15—were measured over a week. It was hypothesized that patients who developed acute muscle wasting would show distinct patterns of change in these mediators.

Design:

A prospective longitudinal observational study of high-risk elective cardiac surgical patients identifying, by ultrasound, those developing muscle wasting.

Setting:

Tertiary cardiothoracic referral center: Royal Brompton Hospital, London, UK.

Patients:

Forty-two patients undergoing elective high-risk cardiothoracic surgery.

Interventions:

Circulating insulin-like growth factor-1, myostatin, and growth and differentiation factor-15 were assayed preoperatively and over the first week postoperatively. The ability of growth and differentiation factor-15 to cause muscle wasting in vitro was determined in C2C12 myotubes.

Measurements and Main Results:

Of the 42 patients, 23 (55%) developed quadriceps atrophy. There was an acute decrease in insulin-like growth factor-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma growth and differentiation factor-15 concentrations increased in all patients. This increase in growth and differentiation factor-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p < 0.01), but recovered in the nonwasting group (p > 0.05). Insulin-like growth factor-1 did not recover in those who developed muscle wasting (day 7 compared with baseline, p < 0.01) but did in the nonwasting group (p > 0.05). Finally, we demonstrated that growth and differentiation factor-15 caused atrophy of myotubes in vitro.

Conclusion:

These data support the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. Growth and differentiation factor-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with ICU acquired paresis and other forms of acute muscle wasting.

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