Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human diaphragm disuse.

Rationale: Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force-generating capacity accompanied by diaphragm myofiber atrophy.

Objectives: Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse.

Methods: Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects).

Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans.

Background: The combination of complete diaphragm inactivity and mechanical ventilation (for more than 18 hours) elicits disuse atrophy of myofibers in animals. We hypothesized that the same may also occur in the human diaphragm.

Methods: We obtained biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before organ harvest (case subjects) and compared them with intraoperative biopsy specimens from the diaphragms of 8 patients who were undergoing surgery for either benign lesions or localized lung cancer (control subjects).

Parasternal intercostal muscle remodeling in severe chronic obstructive pulmonary disease.

Studies in experimental animals indicate that chronic increases in neural drive to limb muscles elicit a fast-to-slow transformation of fiber-type proportions and myofibrillar proteins. Since neural drive to the parasternal intercostal muscles (parasternals) is chronically increased in patients with severe chronic obstructive pulmonary diseases (COPDs), we carried out the present study to test the hypothesis that the parasternals of COPD patients exhibit an increase in the proportions of both slow fibers and slow myosin heavy chains (MHCs). Accordingly, we obtained full thickness parasternal muscle biopsies from the third interspace of seven COPD patients (mean +/- SE age: 59 +/- 4 yr) and seven age-matched controls (AMCs).

Effect of chronic obstructive pulmonary disease on calcium pump ATPase expression in human diaphragm.

We have previously demonstrated that human diaphragm remodeling elicited by severe chronic obstructive pulmonary disease (COPD) is characterized by a fast-to-slow myosin heavy chain isoform transformation. To test the hypothesis that COPD-induced diaphragm remodeling also elicits a fast-to-slow isoform shift in the sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA), the other major ATPase in skeletal muscle, we obtained intraoperative biopsies of the costal diaphragm from 10 severe COPD patients and 10 control subjects. We then used isoform-specific monoclonal antibodies to characterize diaphragm fibers with respect to the expression of SERCA isoforms.

Human diaphragm remodeling associated with chronic obstructive pulmonary disease: clinical implications.

Diaphragm remodeling associated with chronic obstructive pulmonary disease (COPD) consists of a fast-to-slow fiber type transformation as well as adaptations within each fiber type. To try to explain disparate findings in the literature regarding the relationship between fiber type proportions and FEV1, we obtained costal diaphragm biopsies on 40 subjects whose FEV1 ranged from 118 to 16% of the predicted normal value. First, we noted that our exponential regression model indicated that changes in FEV1 can account for 72% of the variation in the proportion of Type I fibers.

Myosin heavy chain and physiological adaptation of the rat diaphragm in elastase-induced emphysema.

Background: Several physiological adaptations occur in the respiratory muscles in rodent models of elastase-induced emphysema. Although the contractile properties of the diaphragm are altered in a way that suggests expression of slower isoforms of myosin heavy chain (MHC), it has been difficult to demonstrate a shift in MHCs in an animal model that corresponds to the shift toward slower MHCs seen in human emphysema.

Methods: We sought to identify MHC and corresponding physiological changes in the diaphragms of rats with elastase-induced emphysema.

Inspiratory loading does not accelerate dystrophy in mdx mouse diaphragm: implications for regenerative therapy.

Since the finding that the mdx mouse diaphragm, in contrast to limb muscles, undergoes progressive degeneration analogous to that seen in Duchenne muscular dystrophy, the relationship between the workload on a muscle and the pathogenesis of dystrophy has remained controversial. We increased the work performed by the mdx mouse diaphragm in vivo by tracheal banding and evaluated the progression of dystrophic changes in that muscle. Despite the establishment of dramatically increased respiratory workload and accelerated myofiber damage documented by Evans blue dye, no change in the pace of progression of dystrophy was seen in banded animals vs.

Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD.

To assess the effect of severe chronic obstructive pulmonary disease (COPD) on the ability of human diaphragmatic myofibers to aerobically generate ATP relative to ATP utilization, we obtained biopsy specimens of the costal diaphragm from seven patients with severe COPD (mean +/- SE; age 56 +/- 1 yr; forced expiratory volume in 1 s 23 +/- 2% predicted; residual volume 267 +/- 30% predicted) and seven age-matched control subjects. We categorized all fibers in these biopsies by using standard techniques, and we carried out the following quantitative histochemical measurements by microdensitometry: 1) succinate dehydrogenase (SDH) activity as an indicator of mitochondrial oxidative capacity and 2) calcium-activated myosin ATPase (mATPase) activity, the ATPase that represents a major portion of ATP consumption by contracting muscle. We noted the following: 1) COPD diaphragms had a larger proportion of type I fibers, a lesser proportion of type IIax fibers, and the same proportion of type IIa fibers as controls.