Rebuttal from Scott K. Powers, Ashley J. Smuder, David Fuller and Sanford Levine

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  • J Physiol 591.21 (2013) p 5263 5263








    C R O S S TA L K

    Rebuttal from Scott K. Powers,Ashley J. Smuder, David Fullerand Sanford Levine

    Scott K. Powers1, Ashley J. Smuder1,David Fuller2 and Sanford Levine31Department of Applied Physiology andKinesiology, University of Florida, Gaines-ville, FL, USA2Department of Physical Therapy, Uni-versity of Florida, Gainesville, FL, USA3Department of Surgery/University ofPennsylvania, and VA Medical Center,Philadelphia, PA, USA


    Drs Sieck and Mantilla have presentedan eloquent argument that diaphragmmuscle fibre atrophy following unilateralphrenicotomy, tetrodotoxin (TTX) nerveblockade or high cervical spinal hemi-section injury does not result from muscleinactivity alone. Nonetheless, we retainour position that when diaphragmaticcontractile work is diminished duringprolonged mechanical ventilation (MV),the ensuing diaphragm fibre atrophy occursprimarily due to decreased diaphragmcontractile activity. In our response toDr Sieck and Mantillas position, wehighlight several fundamental differencesbetween the unilateral denervation modelof diaphragm inactivity and the reduceddiaphragmatic contractile work that occursduring prolonged MV.

    A fundamental difference between thesetwo models of diaphragm inactivity isthat prolonged MV results in atrophy ofall diaphragm muscle fibre types whereasunilateral phrenic denervation promotesa transient hypertrophy of diaphragmatictype I and IIa fibres followed by atrophyof type IIx and IIb fibres. This is a unique

    physiological response as muscle hyper-trophy does not occur in any other model ofskeletal muscle inactivity.

    Another major difference is thatdiaphragm movement patterns differmarkedly between the unilateral phrenicdenervation model of diaphragm inactivityand MV. During MV, both hemidiaphragmsmove synchronously as the lungs inflateand empty. In contrast, following unilateralphrenic denervation, the contralateralhemidiaphragm contracts and shortens,thus eliciting small fibre length changesin the paralysed hemidiaphragm (Zhanet al. 1995). Since muscle fibre size isa highly regulated process controlledby mechanical signals, neurotrophicinfluences, and paracrine signalling whichregulate muscle protein turnover (Rennieet al. 2004), the possibility exists thatdistortion of the paralysed diaphragmelicits an anabolic signalling response topromote hypertrophy.

    Importantly, not all studies reportdiaphragmatic hypertrophy followingdenervation-induced inactivity. Indeed, astudy from Dr Siecks laboratory revealedthat unilateral denervation of the ratdiaphragm results in a net loss of muscleprotein after 5 days (Argadine et al. 2009).It follows that this deficit of muscle proteinshould translate into diaphragm fibreatrophy but unfortunately, this study didnot report diaphragm fibre size. Further,in direct contrast to the rat data, hemi-diaphragm paralysis in humans results inatrophy of diaphragm slow muscle fibreswith atrophy of fast fibres occurring at aslower time course (Welvaart et al. 2011).Interestingly, these results agree with theSieckMantilla initial theoretical argumentthat inactivity-induced diaphragm musclefibre atrophy should occur most rapidly inslow fibres.

    In conclusion, based on our work andthe work of others, we maintain theposition that during prolonged MV, whendiaphragm work against external loads isgreatly diminished, the ensuing diaphragmatrophy is primarily due to decreaseddiaphragm contractile work.

    Call for comments

    Readers are invited to give their viewson this and the accompanying CrossTalkarticles in this issue by submitting a briefcomment. Comments may be posted upto 6 weeks after publication of the article,at which point the discussion will closeand authors will be invited to submit afinal word. To submit a comment, go to;591/21/5263


    Argadine HM, Hellyer NJ, Mantilla CB, ZhanWZ & Sieck GC (2009). The effect ofdenervation on protein synthesis anddegradation in adult rat diaphragm muscle.J Appl Physiol 107, 438444.

    Rennie MJ, Wackerhage H, Spangenburg EE &Booth FW (2004). Control of the size of thehuman muscle mass. Annu Rev Physiol 66,799828.

    Welvaart WN, Paul MA, van Hees HW,Stienen GJ, Niessen JW, de Man FS,Sieck GC, Vonk-Noordegraaf A & OttenheijmCA (2011). Diaphragm muscle fibrefunction and structure in humans withhemidiaphragm paralysis. Am J PhysiolLung Cell Mol Physiol 301,L228L235.

    Zhan WZ, Farkas GA, Schroeder MA, GosselinLE & Sieck GC (1995). Regional adaptationsof rabbit diaphragm muscle fibers tounilateral denervation. J Appl Physiol 79,941950.

    C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society DOI: 10.1113/jphysiol.2013.261552