Signals for Muscular Protein Turnover and Insulin Resistance in Critically Ill Patients: A Narrative Review

Abstract

Sarcopenia in critically ill patients is a highly prevalent comorbidity. It is associated with a higher mortality rate, length of mechanical ventilation, and probability of being sent to a nursing home after the Intensive Care Unit (ICU). Despite the number of calories and proteins delivered, there is a complex network of signals of hormones and cytokines that affect muscle metabolism and its protein synthesis and breakdown in critically ill and chronic patients. To date, it is known that a higher number of proteins decreases mortality, but the exact amount needs to be clarified. This complex network of signals affects protein synthesis and breakdown. Some hormones regulate metabolism, such as insulin, insulin growth factor glucocorticoids, and growth hormone, whose secretion is affected by feeding states and inflammation. In addition, cytokines are involved, such as TNF-alpha and HIF-1. These hormones and cytokines have common pathways that activate muscle breakdown effectors, such as the ubiquitin-proteasome system, calpain, and caspase-3. These effectors are responsible for protein breakdown in muscles. Many trials have been conducted with hormones with different results but not with nutritional outcomes. This review examines the effect of hormones and cytokines on muscles. Knowing all the signals and pathways that affect protein synthesis and breakdown can be considered for future therapeutics.

Keywords: critical illness; cytokines; muscle; proteolysis; sarcopenia.

Figure 1

Anabolic effects on muscle. In this figure, the effects of activation of Insulin Receptor and IGF-R are shown. The white background represents the extracellular space, the green bar the sarcomere membrane, and the green background the cytosol. Red squares represent signals with an inhibitory effect and green squares represent stimulatory ones. The blue square represents hypoglycaemia, which has both inhibitory and stimulatory effects. Green arrows represent the stimulatory effect and red arrows represent the inhibitory effect on different proteins and pathways. Abbreviations: IGF-R: insulin-like growth factor receptor; AMPK = AMP-activated protein kinase.

Figure 2

Catabolic effects on muscle. This figure represents the activation effects of the Glucocorticoid Receptor and the TNF receptor 1. The white background represents the extracellular space, the green bar the sarcomere membrane, and the green background the cytosol. Red arrows represent signals with an inhibitory effect and green arrows represent stimulatory effects on different proteins and pathways. Abbreviations: TNF: tumour necrosis factor; TNFR: tumour necrosis factor receptor.