# The Musculoskeletal Cost of Organ Repair

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $9,580

## Abstract

Project Abstract (R01GM137656)
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 i...

## Key facts

- **NIH application ID:** 10393304
- **Project number:** 3R01GM137656-02S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** LEONIDAS G. KONIARIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $9,580
- **Award type:** 3
- **Project period:** 2020-06-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393304

## Citation

> US National Institutes of Health, RePORTER application 10393304, The Musculoskeletal Cost of Organ Repair (3R01GM137656-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10393304. Licensed CC0.

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