Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

Abstract

Rationale: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.Objectives: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.Methods: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.Measurements and Main Results: Both slow-and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.Conclusions: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

Small‐molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia

“…Consistent with the view that MuRF1 acts as an atrogin, its expression is intimately associated with muscle wasting in numerous clinical conditions (as reviewed in Bodine and Baehr2) or following exposure to pharmacological treatments (e.g. glucocorticoids, inflammatory cytokines, reactive oxygen species7, 8, 9, 10), while its gene inactivation confers partial resistance to muscle wasting conditions 7, 8, 11, 12. Therefore, several approaches have attempted to down‐regulate MuRF1 activity therapeutically, either directly in vitro via targeted inhibition of MuRF1 by a muscle‐specific small molecule13 and adenoviral knockdowns14, 15 or indirectly in vivo via exercise training16 or antioxidant administration17, which resulted in a significant reduction in muscle wasting.…”

Prolonged controlled mechanical ventilation in humans triggers myofibrillar contractile dysfunction and myofilament protein loss in the diaphragm

“…To the best of our knowledge, no studies have been published that document the same effect in non-critically ill humans 37. As an indirect indicator of diaphragm strength, Jaber et al 18 measured tracheal occlusion pressure in response to bilateral phrenic nerve stimulation in intensive care patients undergoing prolonged MV.…”

The Process of Weaning from Mechanical Ventilation

“…The diaphragm seems more sensitive to disuse atrophy than other peripheral skeletal muscles 33 . Several previous studies [33][34][35][36] have shown that critical illness and MV cause atrophy of human diaphragm myofibres. Finally, the abnormalities in muscle function are exacerbated by a decrease in oxygen supply to these muscles, metabolic acidosis, and by certain electrolytic and endocrinological disorders.…”