Direct Assessment of Respiratory and Cardiac Function and Reserve Capacity in a Large Animal Model of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) results in a progressive loss of cardiac and respiratory reserve capacity that is ultimately fatal. Although the molecular deficiency that causes DMD is known, the systemic nature of the disease - along with issues of patient safety - have prevented the direct measurement of reserve and hindered our understanding of the precise mechanisms involved in the functional decline of these two systems. The golden retriever muscular dystrophy (GRMD) dog is an important single-gene animal model of DMD, which exhibits the major functional and cellular hallmarks of the human disease, including progressive loss of respiratory and cardiac function. Here we use surgical and pharmacological techniques to isolate both systems from the confounding influence of background disease, and measure function and reserve directly. We show that cardiac reserve declines as a result of diastolic and systolic dysfunction that is independent of cardiac myocyte necrosis. In the respiratory system we find that the diaphragm undergoes a dramatic process of remodeling that serves to enable the compensatory use of other muscle groups to facilitate breathing, and to protect against energetically unfavorable chest wall motion. Our results shed light on the decline of two muscle-driven systems crucial for life. In addition to providing much needed endpoint measures for assessing the efficacy of therapeutics, we expect these findings to be a starting point for a more precise understanding of cardiopulmonary failure in DMD.