Rationale: Recent work indicates that infections are a major contributor to diaphragm weakness in critically ill mechanically ventilated patients, and that diaphragm weakness is a risk factor for death and prolonged mechanical ventilation. Infections activate muscle calpain, but many believe this is an epiphenomenon and that other proteolytic processes are responsible for infection-induced muscle weakness. Objectives: We tested the hypothesis that muscle-specific overexpression of calpastatin (endogenous calpain inhibitor, CalpOX) would attenuate diaphragm dysfunction in cecal ligation puncture (CLP)-induced sepsis. Methods: We studied: (a) wild type (WT) sham-operated mice, (b) WT CLP-operated mice, (c) CalpOX sham-operated mice and (d) CalpOX CLP-operated mice (n=9-10/group). Twenty-four hours after surgery, we assessed the diaphragm force-frequency relationship, diaphragm mass and total protein content and diaphragm levels of talin and myosin heavy chain (MHC). Results: CLP markedly reduced diaphragm specific force generation (force/CSA) which was prevented by calpastatin overexpression (force averaged 21.4 ± 0.5, 6.9 ± 0.8, 22.4 ± 1.0, and 18.3 ± 1.3 N/cm2, respectively, for WT sham, WT CLP, CalpOX sham, and CalpOx CLP groups, p<0.001). Diaphragm mass and total protein content were similar in all groups. CLP induced talin cleavage and reduced MHC levels; CalpOX prevented these alterations. Conclusions: CLP-induced sepsis rapidly reduces diaphragm specific force generation and is associated with cleavage and/or depletion of key muscle proteins (talin, MHC), effects prevented by muscle-specific calpastatin overexpression. These data indicate that calpain activation is a major cause of diaphragm weakness in response to CLP-induced sepsis.
- Copyright © 2013, Journal of Applied Physiology