A step towards underpinning the molecular signalling events regulating muscle protein loss in critically ill patients

Abstract

Skeletal muscle wasting occurs in patients following trauma, burns, surgical complications and/or sepsis. This inevitable phenomenon affects the whole body as a result of the progressive loss of skeletal muscle mass and strength leading to such higher clinical outcomes as morbidity and mortality. The accelerated degradation of muscle proteins may be caused by insufficient protein intake or infectious and traumatic stress. Indeed, the anabolic and catabolic protein kinases that may be responsible for governing changes in muscle mass are becoming better defined. However, most work in this area is based on cell and animal models, especially in relation to muscle protein turnover. Generally, in vivo human work on muscle loss is performed in models using head-down tilt bed rest, casting, unilateral leg suspension and/or knee immobilization of the leg muscles of healthy younger participants (Phillips et al. 2009). Intervention studies in catabolic patient groups are lacking. Therefore, there is a need to clarify the molecular and cellular mechanisms underlying changes in muscle protein turnover during wasting conditions as observed in critically ill patients, during bed rest, or in sarcopaenic elderly. From a clinical perspective, this will provide novel insights to develop more effective therapeutic strategies to preserve skeletal muscle mass in these patient groups. In a study in a recent issue of The Journal of Physiology, Constantin and colleagues (2011) sought to fill this research gap. Their paper provides novel insights into the molecular mechanisms underlying skeletal muscle wasting in critically ill patients. Key factors that seem to control muscle protein synthesis as well as proteases involved in muscle protein breakdown were investigated. Muscle biopsies were collected from 10 critically ill patients (aged 34–85 years) and 10 age- and sex- matched sedentary, healthy controls. Intramuscular signalling proteins involved in translation initiation of muscle protein synthesis were determined during their stay in the Intensive Care Unit. The study reported an increase in muscle mRNA expression of the anabolic signalling proteins Akt, GSK3, mTORC1, p70S6K and 4E-BP1, which was paralleled by a diminished phosphorylated state in the same signalling proteins. The fact that phosphorylation of p70S6K, a downstream target of mTORC1, was reduced may be of primary importance, as this could be representative of a reduced sensitivity to anabolic stimuli that may exist in critically ill patients. Specifically, the increase in p70S6K phosphorylation, a proxy for activation, has repeatedly been suggested to be indicative of acute muscle protein synthetic response, and might even predict the extent of muscle mass that is gained after resistance training and/or by the provision of amino acids (West et al. 2010). Of course, acute studies simply supply the obligatory framework for long-term intervention studies and thus further work is necessary to examine whether the same holds true in a critically ill subject population. The opposite arm of muscle protein synthesis in the net muscle protein balance equation is muscle protein breakdown (Phillips et al. 2009). Therefore, markers of muscle protein breakdown were studied by Constantin and co-workers (Constantin et al. 2011). They demonstrated higher gene expression and protein levels of the 20S proteasome and the E3-ligases MAFbx and MuRF1 in critically ill patients. Moreover, lysosomal cathepsins were elevated. Therefore, in this study they show that the main proteolytic systems were activated in the muscle. Interestingly, it was reported that mRNA expression and protein concentration of calpain-3, a muscle specific protease, was reduced in the muscle during critical illness. The significance of this finding is not entirely clear as others observed similar effects in certain types of muscular dystrophies as discussed by Constantin and colleagues (2011). It is worth highlighting as well that muscle myostatin mRNA expression was significantly higher in critically ill patients, which corresponded with an increase in myostatin protein expression when compared with the control group. It has been established that myostatin inhibits the phosphorylation of Akt, which eventually leads to muscle protein breakdown. This may be of significance since Akt is an upstream signalling protein of mTORC1, a fundamental control site for the regulation of muscle protein synthesis in humans. Admittedly, static ‘snapshots’ of muscle mRNA expression and protein phosphorylation are not always indicative of dynamic processes, such as muscle protein synthesis and breakdown (Greenhaff et al. 2008). However, the use of a kinetic measurement, as in contemporary stable isotope methodology, requires at least 3–5 h of tracer infusion to accurately measure muscle protein synthesis rates and thus may not be possible in some critically ill patient groups. Moreover, direct determination of muscle protein breakdown can be analytically challenging, and sometimes requires a mathematician to handle the data and ensure accurate results. Constantin et al. (2011) are to be congratulated for taking a step into a subject population that is difficult to study. The workers were able to study critically ill patients in a fasting state. The next logical step would be to examine fed-state responses that could provide valuable information that is needed to assess the impact of food administration on skeletal muscle mass maintenance in critically ill patients. What we know thus far is that feeding of amino acids has a beneficial effect in elderly people, a population that is characterized by accelerated loss of skeletal muscle mass. The latter has been attributed to a blunted muscle protein synthetic response to amino acid and/or protein administration. It remains to be determined if the feeding induced stimulation of muscle protein synthesis rates and/or inhibition of muscle protein breakdown rates are altered in critically ill patients. Our research group has recently infused a cow with amino acid tracers to obtain intrinsically labelled milk proteins (van Loon et al. 2009). Ingestion of these labelled milk proteins can be used as a tool to determine the muscle protein synthetic response in vivo in humans. Furthermore, this may be a valuable tool to determine dynamic measurements of anabolism in a population of subjects where contemporary stable isotope methodology may not be applied easily. Accordingly, dynamic direct measurements of muscle anabolism will allow for another step towards understanding the phenotypic responses of critically ill patients. Ultimately, this information may be fundamental for developing more effective therapeutic strategies for this clinical population.