Wasting is essential: cachexia is driven by a wound-healing adaptation

Abstract

Background: Several explanations have been given for why cachexia occurs in the presence of severe acute wounds and chronic diseases. None of these explanations address the scope of clinical settings in which cachexia has been observed, nor do they account for the failure of nutritional support to reverse cachexia. We hypothesize that induced muscle wasting (IMW) is an adaptation to support wound healing, and when a wound does not heal, prolonged IMW leads to cachexia. Methods: To evaluate this hypothesis, we developed a mathematical model of IMW. In this model, we compared the time needed for wound healing when IMW was present and when it was inhibited. We also measured the relationship between the pathogen growth rate and final patient muscle mass for chronic diseases such as cancer and tuberculosis, demonstrating the onset of cachexia. Finally, we simulated the effects of nutritional support and contrasted the outcomes of when IMW was present and when it was inhibited. Results: Acute wound healing was ~2-6 times longer without IMW than with IMW. For chronic wounds, steady-state muscle mass strongly depended on the growth rate of the pathogenic agent. Inhibiting IMW was more effective at preventing acute muscle mass loss than nutritional support, and the benefit of nutritional support was enhanced by inhibiting IMW. Nutritional support also increased the speed of healing acute wounds when IMW was inhibited. For cancer with high growth rate, giving nutritional support alone had a negligible effect on steady-state muscle mass. But when IMW was inhibited, muscle mass loss was attenuated. With IMW inhibition, nutritional support with the normal diet was able to abrogate muscle mass loss entirely. Conclusions: Inhibiting IMW slows the healing of acute wounds, supporting our hypothesis that IMW is an adaptation to support rapid wound healing. Our experiments demonstrate that nutritional support is insufficient to prevent severe muscle mass loss while IMW continues. But when IMW is inhibited, nutritional support restores normal levels of muscle mass for both acute and chronic wounds, as well as increasing the rate of wound healing. Discovering and developing methods to inhibit IMW for clinical use will be essential to restore patient muscle mass, ease suffering, and reduce mortality.