Critical illness myopathy : effects of specific intervention strategies and molecular mechanisms

Skeletal muscles are a tissue with remarkable adaptability and are essential in the body in many aspects. The homeostasis of the muscles is vital for the maintenance of the body, thus muscle damage is associated with several diseases and leads to a poor quality of life. Acquired muscle weaknesses in the intensive care unit (ICU) is a major complication that occurs in severely ill patients and has a significant impact on the immune system, energy metabolism, amino acid reserves and temperature regulation in the body. Critical illness myopathy (CIM) is a myopathy that results from critical illness and is commonly found in mechanically ventilated ICU patients. It is characterized by paralysis of the limb muscles, atrophy and reduced muscle excitability. The exact cause and underlying mechanisms of the disease remain obscure, hence, the aim of this thesis was to achieve a better understanding of the cellular and molecular mechanisms underlying the muscle wasting and weakness seen in ICU patients with CIM. In accordance with this, a rodent ICU model was used to address the mechanistic and therapeutic aspects of the disease. This thesis has investigated the intracellular pathways controlling the mechanisms underlying muscle wasting in an ICU rat model and the effects of passive mechanical loading. Passive mechanical loading induced significant positive effects on muscle function in the limb muscles and was able to attenuate myosin protein loss, associated with mechanical silencing and CIM. It was also demonstrated that both fission and fusion events as well as mitophagy are significantly affected by mechanosensing. Mitochondria dynamic alterations induced by mechanical silencing were completely counteracted by passive mechanical loading. Additionally it is demonstrated that the temporal pattern and the lack of preferential myosin loss observed in the diaphragm in response to CMV and immobilization differs dramatically to what is occurring in the limb muscles. Further, the response of cranial nerve innervated masseter is also different from that of limb and diaphragm muscles. Early activation of heat shock proteins suggest that an enriched antioxidative profile in the masseter may play a role in the mechanism of preserved masticatory function in CIM.

List of scientific papers

I. Renaud G., Llano-Diez M., Ravara B., Gorza L., Feng H-Z., Jin J-P., Cacciani N., Gustafson A-M., Ochala J., Corpeno R., Li M., Hedström Y., Ford G. C., Nair K. S. and Larsson L. (2013), Sparing of muscle mass and function by passive loading in an experimental intensive care unit model. The Journal of Physiology, 591: 1385–1402.
https://doi.org/10.1113/jphysiol.2012.248724

II. Corpeno Kalamgi R., Salah H., Martinez-Redondo V., Ruas J., Pende M., Sartori R., Sandri M., Guttridge D. and Larsson L. Mechano Cell Signaling Pathways Regulating the Sparing of Muscle mass and Function in an Experimental Intensive Care Unit Model. [Manuscript]

III. Corpeno R., Dworkin B., Cacciani N., Salah H., Bergman H.-M., Ravara B., Vitadello M., Gorza L., Gustafson A.-M., Hedström Y., Petersson J., Feng H-Z., Jin J-P., Iwamoto H., Yagi N., Artemenko K., Bergquist J. and Larsson L. (2014), Time course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat. The Journal of Physiology, 592: 3859–3880.
https://doi.org/10.1113/jphysiol.2014.277962

IV. 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(4): e92622.
https://doi.org/10.1371/journal.pone.0092622