Critical illness myopathy : mechanisms and pharmacological interventions

The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC.

In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partially protected from CIM effects by several mechanisms that reduce proteolysis, including early heat shock protein (HSPs) activation. In paper III, we report that treatment with BGP-15 activates HSP70 and improves the diaphragm muscle fiber function in young but not old rats. In the last paper, we report differences between the new GC, vamorolone and the traditional GC, prednisolone, in the rat ICU model where the former drug shows less negative effects on fast twitch EDL muscle and both show positive effects on the slow twitch soleus muscle. These results emphasize the uniqueness of each muscle response to ICU interventions and also shed some light on a couple of promising pharmacological interventions that may counteract CIM deleterious effects.

List of scientific papers

I. Aare, S., Radell, P., Eriksson, L. I., Akkad, H., Chen, Y. W., Hoffman, E. P., and Larsson, L. (2013). Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model. Physiological Genomics. 45, 312-320.
https://doi.org/10.1152/physiolgenomics.00123.2012

II. Akkad, H., Corpeno, R., and Larsson, L. (2014). Masseter Muscle Myofibrillar Protein Synthesis and Degradation in an Experimental Critical Illness Myopathy Model. Plos One. 9.
https://doi.org/10.1371/journal.pone.0092622

III. Ogilvie, H., Cacciani, N., Akkad, H., and Larsson, L. (2016). Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner. Frontiers in Physiology. 7, 10.
https://doi.org/10.3389/fphys.2016.00417

IV. Akkad, H., Cacciani, N., Llano-Diez, M., Corpeno Kalamgi, R., Tchkonia, T., Kirkland, J.L., Larsson, L. Vamorolone Treatment Improves Skeletal Muscle Outcome in a Critical Illness Myopathy Rat Model. [Submitted]