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.
A fundamental difference between these two models of diaphragm inactivity is that prolonged MV results in atrophy of all diaphragm muscle fibre types whereas unilateral phrenic denervation promotes a transient hypertrophy of diaphragmatic type I and IIa fibres followed by atrophy of type IIx and IIb fibres. This is a unique physiological response as muscle hypertrophy does not occur in any other model of skeletal muscle inactivity.
Another major difference is that diaphragm movement patterns differ markedly between the unilateral phrenic denervation model of diaphragm inactivity and MV. During MV, both hemidiaphragms move synchronously as the lungs inflate and empty. In contrast, following unilateral phrenic denervation, the contralateral hemidiaphragm contracts and shortens, thus eliciting small fibre length changes in the paralysed hemidiaphragm (Zhan et al. 1995). Since muscle fibre size is a highly regulated process controlled by mechanical signals, neurotrophic influences, and paracrine signalling which regulate muscle protein turnover (Rennie et al. 2004), the possibility exists that distortion of the paralysed diaphragm elicits an anabolic signalling response to promote hypertrophy.
Importantly, not all studies report diaphragmatic hypertrophy following denervation-induced inactivity. Indeed, a study from Dr Sieck's laboratory revealed that unilateral denervation of the rat diaphragm results in a net loss of muscle protein after 5 days (Argadine et al. 2009). It follows that this deficit of muscle protein should translate into diaphragm fibre atrophy but unfortunately, this study did not report diaphragm fibre size. Further, in direct contrast to the rat data, hemidiaphragm paralysis in humans results in atrophy of diaphragm slow muscle fibres with atrophy of fast fibres occurring at a slower time course (Welvaart et al. 2011). Interestingly, these results agree with the Sieck–Mantilla initial theoretical argument that inactivity-induced diaphragm muscle fibre atrophy should occur most rapidly in slow fibres.
In conclusion, based on our work and the work of others, we maintain the position that during prolonged MV, when diaphragm work against external loads is greatly diminished, the ensuing diaphragm atrophy is primarily due to decreased diaphragm contractile work.