Abstract  Drs. Sieck and Mantilla have presented an eloquent argument that diaphragm muscle fibre atrophy following unilateral phrenicotomy, tetrodotoxin (TTX) nerve blockade or high cervical spinal hemisection injury does not result from muscle inactivity alone. Nonetheless, we retain our position that when diaphragmatic contractile work is diminished during prolonged mechanical ventilation (MV), the ensuing diaphragm fibre atrophy occurs primarily due to decreased diaphragm contractile activity. In our response to Dr. Sieck and Mantilla's position, we highlight several fundamental differences between the unilateral denervation model of diaphragm inactivity and the reduced diaphragmatic contractile work that occurs during prolonged MV. This article is protected by copyright. All rights reserved