The formation and functional consequences of heterogeneous mitochondrial distributions in skeletal muscle.

Diffusion plays a prominent role in governing both rates of aerobic metabolic fluxes and mitochondrial organization in muscle fibers. However, there is no mechanism to explain how the non-homogeneous mitochondrial distributions that are prevalent in skeletal muscle arise. We propose that spatially variable degradation with dependence on O(2) concentration, and spatially uniform signals for biogenesis, can account for observed distributions of mitochondria in a diversity of skeletal muscle. We used light and transmission electron microscopy and stereology to examine fiber size, capillarity and mitochondrial distribution in fish red and white muscle, fish white muscle that undergoes extreme hypertrophic growth, and four fiber types in mouse muscle. The observed distributions were compared with those generated using a coupled reaction-diffusion/cellular automata (CA) mathematical model of mitochondrial function. Reaction-diffusion analysis of metabolites such as oxygen, ATP, ADP and PCr involved in energy metabolism and mitochondrial function were considered. Coupled to the reaction-diffusion approach was a CA approach governing mitochondrial life cycles in response to the metabolic state of the fiber. The model results were consistent with the experimental observations and showed higher mitochondrial densities near the capillaries because of the sometimes steep gradients in oxygen. The present study found that selective removal of mitochondria in the presence of low prevailing local oxygen concentrations is likely the primary factor dictating the spatial heterogeneity of mitochondria in a diversity of fibers. The model results also suggest decreased diffusional constraints corresponding to the heterogeneous mitochondrial distribution assessed using the effectiveness factor, defined as the ratio of the reaction rate in the system with finite rates of diffusion to that in the absence of any diffusion limitation. Thus, the non-uniform distribution benefits the muscle fiber by increasing the energy status and increasing sustainable metabolic rates.

Chronic bronchitis--measurements and observations over 10 years.

A total of 111 patients with chronic bronchitis were selected for study in 1963. By 1974 only 54 patients were available for clinical examination, chest radiography, and pulmonary function measurements. There was a significantly higher mortality compared with men of the same age and in the same locality, and this was due to cardiorespiratory failure and bronchial carcinoma. Reduction of cigarette smoking, declining atmospheric pollution, and antibiotic treatment have reduced the 24-hour sputum volume of these patients. The initial one-second forced expiratory volume (FEV1) and vital capacity were significantly lower in those patients who later died from cardio-respiratory failure. The duration of antibiotic treatment and the smoking record have not significantly affected the decline of the FEV1 with advancing age. The transfer factor (diffusing capacity) for carbon monoxide (TF) has declined more in those who continued to smoke. Of the 54 patients 14 had radiological evidence of emphysema initially. This has shown little change over 10 years.

Five-year winter chemoprophylaxis for chronic bronchitis.

Seventy-nine patients with chronic bronchitis were randomly allotted to four treatment regimens-placebo throughout the winter months for five years; tetracycline for the first two winters and placebo for the next three; placebo for the first two winters and tetracycline for the next three; and tetracycline for five winters. In addition all groups recevied a five-day course of tetracycline for any acute exacerbation. There was a significant reduction in the number of exacerbations among the more susceptible patients-that is, those who suffered more than one exacerbation each winter. Though the average decline in F.E.V.(1) over the five-year period was less in the treated groups this was not statistically significant. There was no significant difference between the groups in respect of lung volumes, diffusing capacity, and blood gases.