Ventilatory dysfunction in mdx mice: impact of tumor necrosis factor-alpha deletion.

Abstract

Muscular dystrophy is associated with inflammation and fiber necrosis in the diaphragm that may alter ventilatory function. The purpose of this study was to determine to what extent in vivo ventilatory function in dystrophic (mdx) mice was compromised and to assess the impact of deletion of tumor necrosis factor-alpha (TNF-alpha), a known proinflammatory cytokine, on ventilatory function, diaphragm contractility, and myosin heavy chain (MHC) distribution in 10-12-month-old mdx mice. Although the resting ventilatory pattern did not significantly differ between control and mdx mice, the ventilatory response to hypercapnia in mdx mice was significantly attenuated. Elimination of TNF-alpha significantly improved the hypercapnic ventilatory response and diaphragm muscle maximal isometric force. Long-term TNF-alpha deletion also altered the myosin heavy chain isoform profile of the diaphragm. These data indicate that a blunted ventilatory response to hypercapnia exists in mdx mice, and that TNF-alpha influences the progressive deterioration of diaphragm muscle in mdx mice.