Lipid Overload: Trigger or Consequence of Mitochondrial Oxidative Stress in Ventilator-induced Diaphragmatic Dysfunction?

Invasive mechanical ventilation (MV) is a life-saving measure applied to critically ill patients to achieve adequate pulmonary gas exchange and unload excessive respiratory muscle work. However, both animal (1) and recent human (2) studies have demonstrated that complete diaphragm muscle unloading or inactivity during invasive MV induces a rapid and profound loss of diaphragm muscle force-generating capacity. In 2004, the loss of diaphragmatic force in the course of MV was termed ventilator-induced diaphragmatic dysfunction (VIDD) (3). In 2008, Levine and colleagues (4) demonstrated that VIDD occurs in critically ill patients and is characterized by marked diaphragm atrophy of both slow-twitch and fast-twitch fibers, with evidence of both oxidative stress and proteolysis. In several recent studies using animal models (5, 6), investigators have reported that redox disturbances in diaphragmatic fibers play a key role in VIDD. In particular, diaphragmatic inactivity promotes the production of reactive oxygen species (ROS) from the mitochondria, and importantly, the administration of mitochondrially targeted antioxidants protects against VIDD.

In this issue of the Journal, Picard and colleagues (pp. 1140–1149) provide a novel, in-depth study of the role of mitochondrial dysfunction in humans subjected to diaphragm inactivity during the course of invasive MV (7). They obtained diaphragmatic muscle fibers from brain-dead organ donors who had been mechanically ventilated for 15–176 hours and compared them with control patients who were mechanically ventilated for 2–3 hours during thoracotomy. They found that diaphragms from subjects receiving prolonged mechanical ventilation had reduced levels of respiratory chain enzymes and impaired mitochondrial biogenesis. These changes were associated with mitochondrial DNA deletions and decreased levels of peroxiredoxin-3, a mitochondrial scavenger of peroxides. These findings suggest that mitochondrial-generated oxidative stress plays a key role in the development of VIDD. What, then, is the trigger for mitochondrial-generated ROS production? The authors suggested a model of metabolic oversupply as the trigger for mitochondrial-generated ROS production. They hypothesized that in mechanically ventilated subjects, a state of energetic substrate oversupply develops in diaphragm muscle fibers when the workload is taken over by the ventilator. In support of this hypothesis, they showed excess lipid accumulation in the diaphragm muscle of mechanically ventilated subjects. They also found that two important proteins regulated by energy imbalances were down-regulated: AMPK and Sirtuin-1, both known to regulate mitochondrial metabolism and biogenesis (8). Based on these data, the authors suggest that MV induces a state of energy imbalance in the diaphragm that leads to lipid accumulation, increased mitochondrial oxidative stress, and decreased AMPK and Sirtuin activities, resulting in mitochondrial dysfunction and reduced mitochondrial biogenesis. However, this hypothesis was not supported by their murine model of lipid oversupply and mechanical ventilation, as they did not find a significant reduction in diaphragmatic force when compared with MV alone.

As a matter of fact, the relationship between lipid accumulation and mitochondrial dysfunction is controversial. In other models of lipid overload (e.g., models of insulin resistance in skeletal muscle), it has been postulated that mitochondrial abnormalities lead to the accumulation of ectopic lipids (9), in contrast to the hypothesis presented by Picard and coworkers, in which lipid accumulation seems to precede mitochondrial dysfunction in the animal model. Further limitations of the study include the lack of information with respect to body composition, the presence of metabolic syndrome, and the mode of mechanical ventilation. Similar to previous studies (2, 4), the subjects consisted of brain-dead organ donors—a population that differs from typical critically ill patients receiving prolonged MV in the intensive care unit. This poses the question of whether, in those patients, diaphragm muscle metabolism including redox balance and mitochondrial function might result from the loss of central nervous system input. Nevertheless, it must be acknowledged that biopsies from the diaphragm, the primary respiratory muscle, can only be obtained from brain-dead organ donors.

The findings by Picard and colleagues are clinically relevant, but they will require validation and further investigation before they can be translated to the care of critically ill patients receiving MV. Diaphragm muscle weakness due to mitochondrial dysfunction stimulated by energy oversupply might contribute to weaning failure, which if prolonged to more than 7 days, is associated with an increased risk of death (10, 11). Further research will be required to assess whether the concept of lipid/energy oversupply is associated with other cellular mechanisms such as autophagy (12), apoptosis (13), and enhanced protein catabolism (4), which were shown to be major contributors to VIDD. Finally, new studies should also aim to shed light on whether scavengers of reactive oxygen species and antioxidants may offer novel therapeutic strategies to the critically ill patients with VIDD.