Final Report Summary - NUTRI-CARE (Nutri-CARE: Nutrient restriction during Critical illness: from induction of Autophagy to Repression of aberrant Epigenetic alterations)
Understanding the underlying molecular and cellular mechanisms of the apparent damage-induced “reprogramming” and the benefit of tolerating a macronutrient deficit is crucial in order to develop interventions to prevent and/or treat these consequences of critical illnesses. We hypothesized that activation of autophagy and repression of aberrant epigenetic alterations play a major role. We aimed to investigate (1) the role of autophagy in recovery from critical illness; (2) the degree of genetic predisposition within the mitochondrial genome and nuclear genes controlling mitochondrial turnover and autophagy for recovery from critical illness and its chronic sequellae; and (3) the impact of tolerating a macronutrient deficit early in the course of critical illness on epigenetic alterations (features that modify chromatin structure and/or affect gene expression without changing the primary DNA sequence) during critical illness and how these relate to recovery from organ failure and to long-term sequellae.
We demonstrated that tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness in ICU. With use of experimental models we demonstrated an important protective role of autophagy in critical illness. We are currently analyzing the data we obtained with regard to genetic predisposition. We also linked epigenetic changes to increased formation of active bone-resorbing cells. Further detailed epigenetic studies in different organs/cell types are ongoing. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.