# The Musculoskeletal Cost of Organ Repair

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $414,221

## Abstract

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 thera...

## Key facts

- **NIH application ID:** 9998362
- **Project number:** 1R01GM137656-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** LEONIDAS G. KONIARIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $414,221
- **Award type:** 1
- **Project period:** 2020-06-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998362

## Citation

> US National Institutes of Health, RePORTER application 9998362, The Musculoskeletal Cost of Organ Repair (1R01GM137656-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998362. Licensed CC0.

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