To the editor
Calcineurin is recognized as a crucial, though not the sole, signalling intermediate in the regulation of skeletal muscle fibre hypertrophy in mice and rats1,2,3. Recently, Bodine and colleagues4 refuted a function for calcineurin in growth because, unlike us (Fig 1b,c in ref. 1), they were unable to prevent hypertrophy of overloaded muscle fibres with the calcineurin inhibitors, cyclosporin A (CsA) or FK506.
Their failure to block fibre hypertrophy may be because they injected a lower dose of CsA, administered both inhibitors only once daily, initiated drug treatments 1 day later, and used different drug vehicles compared to our regime1,2. They show average calcineurin activities to be 20% lower after CsA treatment and unchanged by CsA in overloaded muscles4, compared to our observation of 65% inhibition with a higher dose of CsA (Fig. 1a)3. Clear dose-dependent effects of CsA on calcineurin activity and CsA blood levels exist (Fig. 1b). Furthermore, their report of increased muscle mass after 1 week of overload-FK506 treatment may be caused by inflammation, a well-documented characteristic of the overload model5,6,7, emphasizing that wet mass is not a reliable measure of muscle hypertrophy1. Indeed, muscle protein content is only higher at 15 days and decreased protein concentrations recovered by 30 days of overload6,7. Finally, the authors attribute our CsA drug effects to general toxicity. As stated1, animal growth and daily locomotor activity levels were unaffected by CsA treatment (Fig. 1c,d). Given these arguments, and our recent demonstration of an extensive calcineurin-mediated dephosphorylation of NFAT and MEF2 during overload3, it is premature to rule out a function for calcineurin in skeletal muscle growth.
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Dunn, S., Simard, A., Prud'homme, R. et al. Calcineurin and skeletal muscle growth. Nat Cell Biol 4, E46 (2002). https://doi.org/10.1038/ncb0302-e46a
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DOI: https://doi.org/10.1038/ncb0302-e46a
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