Inhibiting autophagy prevents diaphragm weakness in patients on mechanical ventilation

By John Murphy, MDLinx
Published January 13, 2016

Key Takeaways

Prolonged mechanical ventilation results in the rapid onset of proteolysis, leading to both diaphragmatic atrophy and contractile dysfunction. To make matters worse, mechanical ventilation-induced diaphragmatic weakness increases the difficulty of weaning patients from the ventilator.   

In study findings presented September 10, 2015 at the Physiological Bioenergetics: From Bench to Bedside conference, held in Tampa, FL, researchers identified the cause of the diaphragmatic weakness on a cellular level. This information could lead to strategies to help prevent ventilator-related diaphragm damage. 

The investigators previous research linked weakness in the diaphragm to dysfunction in the cell’s mitochondria and production of reactive oxygen species. “This results in oxidative damage to diaphragm proteins, leading to increased breakdown of proteins in the diaphragm and wasting (atrophy) of the fibers in the diaphragm,” said the study’s lead author Ashley Smuder, PhD, of the Department of Applied Physiology and Kinesiology at the University of Florida, in Gainesville, FL.

But what researchers didn’t know is whether mechanical ventilation-induced increased autophagy occurs as a protective mechanism to degrade dysfunctional mitochondria or if increased autophagy exacerbates mitochondrial dysfunction.

“The goal of this study was to determine the effects of mechanical ventilation-induced activation of the autophagy/lysosomal system on ventilator-induced diaphragm mitochondrial dysfunction,” Dr. Smuder said.

In lab experiments, the researchers inhibited mechanical ventilator-induced autophagy by overexpressing mutated autophagy-related protein 5 (ATG5) in the diaphragm of rats. They found that inhibiting autophagy prevented the mechanical ventilator-induced reduction in mitochondrial oxygen consumption.

Furthermore, transduction of mutated ATG5 prevented mechanical ventilator-induced increase in both mitochondrial emission of reactive oxygen species and caspase-3 activation.

“Our results demonstrate that inhibiting autophagy during mechanical ventilation can reduce mitochondrial dysfunction and prevent diaphragm atrophy and contractile dysfunction,” Dr. Smuder said.

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