Role of intrinsic aerobic capacity and ventilator-induced diaphragm dysfunction

Abstract

Prolonged mechanical ventilation (MV) leads to rapid diaphragmatic atrophy and contractile dysfunction, which is collectively termed "ventilator-induced diaphragm dysfunction" (VIDD). Interestingly, endurance exercise training prior to MV has been shown to protect against VIDD. Further, recent evidence reveals that sedentary animals selectively bred to possess a high aerobic capacity possess a similar skeletal muscle phenotype to muscles from endurance trained animals. Therefore, we tested the hypothesis that animals with a high intrinsic aerobic capacity would naturally be afforded protection against VIDD. To this end, animals were selectively bred over 33 generations to create two divergent strains, differing in aerobic capacity: high-capacity runners (HCR) and low-capacity runners (LCR). Both groups of animals were subjected to 12 h of MV and compared with nonventilated control animals within the same strains. As expected, contrasted to LCR animals, the diaphragm muscle from the HCR animals contained higher levels of oxidative enzymes (e.g., citrate synthase) and antioxidant enzymes (e.g., superoxide dismutase and catalase). Nonetheless, compared with nonventilated controls, prolonged MV resulted in significant diaphragmatic atrophy and impaired diaphragm contractile function in both the HCR and LCR animals, and the magnitude of VIDD did not differ between strains. In conclusion, these data demonstrate that possession of a high intrinsic aerobic capacity alone does not afford protection against VIDD. Importantly, these results suggest that endurance exercise training differentially alters the diaphragm phenotype to resist VIDD. Interestingly, levels of heat shock protein 72 did not differ between strains, thus potentially representing an important area of difference between animals with intrinsically high aerobic capacity and exercise-trained animals.

Keywords: mitochondria; muscle atrophy; oxidative stress; reactive oxygen species.

Copyright © 2015 the American Physiological Society.

Figures

Fig. 1.

In vitro diaphragmatic force-frequency response. Values are means ± SE. MV, mechanical ventilation; LCR, low-capacity runner; HCR, high-capacity runner; CON, control group. #P < 0.05; MV-LCR and MV-HCR significantly different from CON-LCR and CON-HCR. No differences between CON-LCR and CON-HCR or MV-LCR and MV-HCR at any stimulation frequencies examined (n = 10/group). Note: because of similar values between control groups, symbols may be difficult to differentiate.

Fig. 2.

Fiber cross-sectional area (CSA) in diaphragm muscle myofibers from LCR and HCR CON or animals exposed to 12 h of MV. Values are normalized to body mass. Note that 12 h of MV caused significant atrophy of all fiber types for both strains. Values are means ± SE. *P < 0.05; MV significantly different from control within strain (HCR vs. LCR; n = 8–9/group).

Fig. 3.

Isolated diaphragm mitochondria respiratory control ratio (RCR) from both LCR and HCR animals. Mitochondria were isolated from acutely anesthetized animals (CON) or animals exposed to 12 h of MV. RCR was obtained by diving state 3 and state 4 respiration. Data were obtained using pyruvate/malate as the substrate. Values are means ± SE. *P < 0.05; MV significantly different from control within strain (HCR vs. LCR; n = 7–9/group).

Fig. 4.

Relative protein abundance of primary antioxidants in diaphragm muscle. Values are mean percent change compared with LCR control ± SE and normalized to α-tubulin. Representative Western blots for the antioxidants are shown above the respective graphs. A: protein levels of SOD1 (CuZn-SOD). B: protein levels of SOD2 (MnSOD). C: protein levels of GPX1. D: protein levels of catalase. ¶P < 0.05; main effect of strain (HCR vs. LCR). #P < 0.05; main effect of treatment (CON vs. MV). †P < 0.05; difference between strains within CON (HCR vs. LCR). ŦP < 0.05; difference between strains within MV (HCR vs. LCR; n = 9–10).

Fig. 5.

Assessment of citrate synthetase (CS) relative protein abundance in diaphragm muscle. Values are mean percent change compared with LCR control ± SE and normalized to α-tubulin. A representative Western blot is shown at top. ¶P < 0.05; main effect of strain (HCR vs. LCR). #P < 0.05; main effect of treatment (CON vs. MV). †P < 0.05; difference between strains within CON (HCR vs. LCR). ŦP < 0.05; difference between strains within MV (HCR vs. LCR). *P < 0.05; difference between treatment within HCR (CON vs. MV; n = 9–10).

Fig. 6.

Relative protein abundance of heat shock protein 72 (HSP72). Values are mean percent change compared with LCR control ± SE and normalized to α-tubulin. A representative Western blot is shown at top graph. Note: no differences exist between any groups (n = 8–10/group).