Surviving critical injury or surgery requires an essential catabolic recovery period that typically extends from days to weeks. This catabolism, defined as ?the breakdown of existing molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions? (Royal Chemical Society), is systemic, activates rapid loss of skeletal muscle during the period of organ repair and regeneration, and resolves with recovery. Cuthbertson originally reported the rapid loss of muscle in long-bone fracture patients in 1930, first terming it ?ebb and flow?. This process has subsequently been termed ?hypermetabolism? or ?the adrenergic-corticoid phase?. Work by Rhoads and others found that this catabolic response, rather than nutritional intake, drives repair and regeneration of tissues following critical injury (including elective surgery). In contrast to starvation, the post-injury catabolic response is proportional to the degree of injury, supports ongoing energy needs, and supplies critical substrates (amino acids, fats) to repair, and regenerate injured organs and tissues. Serious injuries including major trauma, liver resection, and burns can require catabolic responses over days to weeks to fully recover. Although optimizing preoperative nutrition improves surgical outcomes, it does not prevent muscle catabolism. Conversely, an impaired catabolic response is associated with increased morbidity and mortality. Although current literature has focused on pathological persistence of the catabolic response and energy expenditure following injury, particularly after burns, acute catabolism is essential to survive injury. To date, little work has addressed how the recovery from critical injury induces the release of metabolic substrates from muscle and other stores to meet the acute requirement for the repair and regeneration of damaged organs. Our data indicate that injured organs are repaired at the expense of skeletal muscle mass. Furthermore, we found that tissue repair activates the catabolism of muscle partly through a liver mechanism. Understanding how we heal following injury, and the role of muscle crosstalk in this process will open new paradigms for therapies after critical injury. We hypothesize that post-injury catabolism of muscle is: 1) the critical systemic response needed to supply substrates for the repair of damaged organs, 2) universal after critical injury, including both controlled (surgery) and traumatic injury, 3) molecularly similar to muscle wasting of cachexia in cancer and other disorders, including in activation of atrogenes like MuRF1, 4) mediated by the injured organs through reciprocal, feed-forward Interleukin-6 (IL-6)/JAK/STAT to YAP/TAZ signaling, and 5) amenable to pharmacologic interventions. Here we will 1) Define mechanisms of organ crosstalk in liver growth and muscle wasting; 2) Define mechanisms of organ crosstalk via the IL-6/YAP/TAZ pathway in serious burn injury and investigate the therapeutic potential of YAP/TAZ modulation to augment recovery from injury; 3) Interrogate the IL-6/YAP/TAZ pathway in blood and muscle from patients with major liver resection or critical injury requiring delayed abdominal closure.

Public Health Relevance

Following surgery or traumatic injury, the body requires a large quantity of amino acids and fats to regenerate and heal damaged tissues and organs. This process, however, generally occurs during a time of impaired eating and works through a mechanism whereby the body massively catabolizes tissues including muscle and fat; this application seeks to understand the molecular and cellular processes involved in organ cross-talk after injury, focusing on the mediators IL-6, YAP and TAZ in the inter-organ communication of tissues, organs, and muscle in the context of severe injury.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1)
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Garcia, Martha
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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