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*

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 (IGF-1), myostatin and growth and differentiation factor-15 (GDF-15), were measured over a week. It was hypothesised 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 centre: Royal Brompton Hospital, London, UK.Patients: 42 patients undergoing elective high-risk cardiothoracic surgery.Interventions: Circulating IGF-1, myostatin and GDF-15 were assayed pre-operatively and over the first week post-operatively. The ability of GDF-15 to cause muscle wasting in vitro was determined in C2C12 myotubes. Measurements and main results: 23 of 42 patients (55%) developed quadriceps atrophy. There wasan acute decrease in IGF-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma GDF-15 concentrations increased in all patients. This increase in GDF-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p<0.01), but recovered in the non-wasting group (p>0.05). IGF-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 GDF-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. GDF-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with Intensive care unit acquired paresis and other forms of acute muscle wasting.Abstract word count: 292

Serum concentrations of insulin-like growth factor-1, members of the TGF-beta superfamily and follistatin do not reflect different stages of dynapenia and sarcopenia in elderly women

“…To our knowledge, no studies dealing with GDF-15 in the context of sarcopenia or dynapenia have been published to date but Bloch et al recently demonstrated that GDF-15 induces fiber atrophy in cultured C2C12 myotubes. Moreover, these authors showed a significant association between GDF-15 and acute muscle wasting following the physiological stress of cardiac surgery (Bloch et al, 2013). Similarly, GDF-15 was also elevated in patients with anorexia and cachexia (Tsai et al, 2012).…”

Can Sarcopenia Quantified by Ultrasound of the Rectus Femoris Muscle Predict Adverse Outcome of Surgical Intensive Care Unit Patients as well as Frailty? A Prospective, Observational Cohort Study

“…Patients in whom the lines of the RF muscle were not well defined due to soft-tissue edema were excluded (n = 3). 26 To test the accuracy of measurements, 9 patients underwent repeat measurements of right RF CSA on 2 separate occasions during the same day. The mean (SD) bias and 95% limits of agreement were −0.08 (0.44) cm 2 and −0.94 to −0.78 cm 2 .…”

Biomarkers in sarcopenia: A multifactorial approach

“…Protein and mRNA levels of Growth Differentiation Factor-15 (GDF-15), another member of the TGFβ superfamily, are related to muscle atrophy in patients undergoing cardiac surgery (Bloch et al, 2013). Interestingly, an increased expression of GDF-15 was associated with a reduced expression of some microRNAs involved in the regulation of muscle growth in patients hospitalized in intensive care (Bloch et al 2015).…”