Muscle regeneration after sepsis

 Bouglé, A. et al. Critical Care. 2016 20:131. Published online: 19 May 2016

Severe critical illness is often complicated by intensive care unit-acquired weakness (ICU-AW), which is associated with increased ICU and post-ICU mortality, delayed weaning from mechanical ventilation and long-term functional disability. Several mechanisms have been implicated in the pathophysiology of ICU-AW, but muscle regeneration has not been investigated to any extent in this context, even though its involvement is suggested by the protracted functional consequences of ICU-AW. Recent data suggest that muscle regeneration could be impaired after sepsis, and that mesenchymal stem cell treatment could improve the post-injury muscle recovery.

The primary functions of skeletal musculature are locomotor activity, postural behavior, and breathing. Severe critical illness is often complicated by intensive care unit-acquired weakness (ICU-AW), which is clinically characterized by bilateral and symmetrical limb weakness and is related to a myopathy and/or axonal polyneuropathy. ICU-AW affects between 25 % and 60 % of patients mechanically ventilated for more than 7 days [1], and is associated with increased ICU and post-ICU mortality, delayed weaning from mechanical ventilation and long-term functional disability [2]. Most patients who develop ICU-AW have been admitted for a sepsis episode, and the main risk factors for ICU-AW include the severity of critical illness, immobilization, hyperglycemia, and the use of some medications, including steroids and neuromuscular agents, although this is somewhat controversial.

The pathophysiology of critical illness myopathy is thought to involve the following mechanisms: 1) impairment of muscular membrane excitability, secondary to a dysregulation of sodium channel gating [3]; 2) mitochondrial dysfunction leading to bioenergetic failure and oxidative stress [4]; and 3) proteolysis, mainly related to an activation of the ubiquitin-proteasome pathway [5]. These mechanisms can be triggered by various factors, notably systemic inflammatory mediators, endocrine dysfunction, immobilization, some drugs, and electrolyte disturbances. The protracted functional consequences of ICU-AW indicate that muscle regeneration is also impaired. Surprisingly, muscle regeneration, which essentially depends on the muscle stem cells (also called satellite cells (SC)), has not been extensively investigated in the context of critical illness. SC that are located at the periphery of the muscle fiber [6] are activated in response to any muscle injury and then proliferate and differentiate to repair or replace the damaged fibers, and also self-renew to replenish the muscle stem cell reservoir [7].

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