Muscle protein and adipose catabolism after burn or other life-threatening injury is likely an acute, adaptive response to preserve organ function and promote survival. However, persistent cachexia in the convalescent phase is pathological in itself. Hypermetabolism and catabolism of skeletal muscle mass for up to 2 years after burn injury renders patients vulnerable to injury and infection, retards wound healing, reduces overall function and diminishes quality of life. Myostatin is a skeletal muscle-specific member of the Transforming Growth Factor- 2 superfamily and a potent, tonic muscle growth inhibitor .Our long term goal is to define the key regulatory pathways mediating muscle wasting after burn injury for the purpose of developing therapeutics. The objective of this application is to determine the role of the myostatin signaling pathway in muscle wasting after burn injury. Our hypothesis is that myostatin and related ligands promote muscle wasting after burn injury, and that altering myostatin family signaling after burn will change burn survival, muscle mass and function. In the acute post-burn period, myostatin signaling and muscle wasting may facilitate survival. In the longer term, myostatin action and muscle wasting becomes maladaptive, reducing function and increasing vulnerability. We base this hypothesis on considerable preliminary data. We developed a mouse model of burn injury that causes long- term hyperinflammation and catabolism despite hyperphagia. Myostatin family signaling was increased in skeletal muscle after burn. Paradoxically, myostatin null mice exhibited enhanced wasting but also increased survival after burn. Administration of a myostatin inhibitor reduced muscle loss after burn injury. However, abolishing signaling from all myostatin-family ligands using a dominant negative ACVR2B transgenic resulted in 100% mortality after burn injury. These data indicate that myostatin family signaling plays an important, temporally regulated role in muscle size control after burn-injury. To study myostatin in burn, we have assembled a highly interactive, multidisciplinary team. The PI is a molecular biologist and expert in muscle wasting and the co-investigators are the world-leader in myostatin research, a highly accomplished academic surgeon-scientist, and the director of one of the country's largest and busiest burn centers. Each is necessary for the ultimate translation of these findings to therapeutics. Together we will determine the role of myostatin and myostatin-related ligand activity in burn-induced muscle wasting;determine the role of the myostatin family receptors ACVR2 and ACVR2B in burn-induced muscle wasting;and determine the role of SMAD2 activity 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. 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 #
3R01GM092758-01A1S1
Application #
8240616
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
2010-08-01
Budget End
2011-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$27,217
Indirect Cost
Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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
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
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