Hypermetabolism and catabolism of skeletal muscle mass persist for up to 2 years after burn injury, rendering patients vulnerable to injury and infection, retarding wound healing, reducing overall function and diminishing quality of life. We seek to understand the molecular pathways leading to muscle loss after burn injury in order to identify rational interventions to reduce wasting, speed recovery and improve survival. The main goal of this proposal is to explore the role of the myostatin family of muscle growth regulators in burn cachexia. To this end, we have assembled a multidisciplinary team of the PI, a molecular biologist and expert in muscle wasting, along with the world-leader in myostatin, a surgeon-scientist, and the director of one of the country's largest and busiest burn centers, with the ultimate goal of translating our findings to therapeutics. Our preliminary data in a mouse model of chronic burn wasting show that myostatin family signaling was increased in skeletal muscle in burn cachexia, that myostatin null mice exhibited enhanced survival after burn, and that administration of a myostatin inhibitor enhanced growth and recovery of muscle mass after burn injury. However, abolishing signaling from all myostatin-family ligands using a dominant negative receptor transgenic resulted in 100% mortality after burn injury. These data indicate the following overall hypothesis: Myostatin-family signaling contributes to muscle wasting after burn injury through growth-inhibitory and pro-catabolic effects on mature myofibers. Inhibiting myostatin-family signaling in the chronic catabolic state will accelerate recovery of muscle mass and preserve myofiber protein. However, myostatin-family induced catabolism in the immediate post-burn period is important for survival.
The Specific Aims are: 1) to interrogate the mechanisms modulating myostatin and other ACVR2B ligand signaling and target genes in burn-induced muscle wasting; 2) to test how global inhibition (genetic and pharmacologic) of myostatin or ACVR2B ligands in burn injury alters survival, muscle mass, SMAD and AKT activation, and proteolytic pathways; and 3) to test how manipulation of myostatin pathway signaling in individual myofibers alters myofiber size in normal muscle and in burn induced muscle wasting.

Public Health Relevance

The studies will result in new insights into the molecular pathways by which myostatin and related ligands regulate muscle mass in normal physiology and in burn wasting. Furthermore, these studies are likely to identify novel genes involved in regulating muscle growth. They are essential pre-clinical studies for determining the potential clinical benefit of modulating myostatin for increasing survival and function after burn injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM092758-03
Application #
8366782
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2010-08-01
Project End
2015-05-31
Budget Start
2011-08-01
Budget End
2012-05-31
Support Year
3
Fiscal Year
2011
Total Cost
$264,791
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Milgrom, Daniel P; Koniaris, Leonidas G; Valsangkar, Nakul P et al. (2018) An Assessment of the Academic Impact of Shock Society Members. Shock 49:508-513
Kays, Joshua K; Shahda, Safi; Stanley, Melissa et al. (2018) Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer. J Cachexia Sarcopenia Muscle 9:673-684
Jin, Xiaoling; Zimmers, Teresa A; Jiang, Yanlin et al. (2018) Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet-induced obese mice. Surgery 163:1264-1271
Pons, Marianne; Koniaris, Leonidas G; Moe, Sharon M et al. (2018) GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure. Surgery 164:262-273
Sato, Amy Y; Richardson, Danielle; Cregor, Meloney et al. (2017) Glucocorticoids Induce Bone and Muscle Atrophy by Tissue-Specific Mechanisms Upstream of E3 Ubiquitin Ligases. Endocrinology 158:664-677
Bell, Teresa M; Valsangkar, Nakul; Joshi, Mugdha et al. (2017) The Role of PhD Faculty in Advancing Research in Departments of Surgery. Ann Surg 265:111-115
Zimmers, Teresa A; Jiang, Yanling; Wang, Meijing et al. (2017) Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. Basic Res Cardiol 112:48
Zimmers, Teresa A; Jin, Xiaoling; Zhang, Zongxiu et al. (2017) Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice. Am J Physiol Endocrinol Metab 313:E440-E449
Ogunbileje, John O; Porter, Craig; Herndon, David N et al. (2016) Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma. Am J Physiol Endocrinol Metab 311:E436-48
Bell, Teresa M; Valsangkar, Nakul; Joshi, Mugdha et al. (2016) The Role of PhD Faculty in Advancing Research in Departments of Surgery. Ann Surg :

Showing the most recent 10 out of 27 publications