Cachexia is a complex metabolic disorder associated with several pathophysiological conditions including cancer. This syndrome is characterized by anorexia, anemia, weight loss, increases in metabolic rate, and tissue breakdown deriving predominantly from adipose and skeletal muscle. In cancer, the majority of patients suffer from cachexia and estimates suggest that nearly one third of mortalities result from cachexia rather than tumor burden. Catabolic factors thought to play a prominent role in cancer cachexia are proinflammatory cytokines, produced from the tumor itself or from the host immune system in response to the tumor. Specifically, tumor necrosis factor alpha (TNF) is strongly implicated in regulating skeletal muscle wasting. Other cytokines, most notably interleukin-1beta, interleukin-6 and interferon-gamma (IFN), are believed to function in concert with TNF to fully coordinate the breakdown of muscle. The molecular basis of skeletal muscle wasting associated in cancer remains poorly defined. The minimum numbers of cytokines required to induce muscle loss or the downstream signaling molecules that mediate cytokine action have not been identified. NF-kappa B (NF-kappaB) is a ubiquitously expressed transcription factor that is potently activated by TNF. This signaling molecule functions as a negative regulator of skeletal muscle cell differentiation. TNF-induced activation of NF-kappaB blocks muscle differentiation by inhibiting the expression of MyoD, a skeletal muscle-specific transcription factor involved in myogenic differentiation. In mature muscle, TNF requires the additional activity of IFN to induce myofibrillar protein loss, and importantly this regulation is dependent on NF-kappaB activity. To goal of this proposal is to gain insight on how TNF and IFN signal to NF-kappaB in skeletal muscle, and to investigate the relevance of this signaling pathway with respect to muscle wasting.
Aim 1 will utilize the C2C12 cell culture system to characterize the mechanism by which cytokines and NF-kappaB cause loss of myofibrillar proteins.
Aim 2 will extend in vitro studies to identify how NF-kappaB activity is regulated by TNF and IFN in muscle cells, and which other signaling molecules lie in this transduction pathway that are required for muscle wasting.
Aim 3 will utilize animal models to investigate the role of these cytokines and NF-kappaB in muscle wasting in vivo. Completion of these aims may identify molecular targets in cachexia treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098466-03
Application #
6850697
Study Section
Special Emphasis Panel (ZRG1-CAMP (01))
Program Officer
Dunn, Barbara K
Project Start
2003-03-07
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$245,219
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Damrauer, Jeffrey S; Stadler, Michael E; Acharyya, Swarnali et al. (2018) Chemotherapy-induced muscle wasting: association with NF-?B and cancer cachexia. Eur J Transl Myol 28:7590
He, Wei A; Berardi, Emanuele; Cardillo, Veronica M et al. (2013) NF-?B-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia. J Clin Invest 123:4821-35
Bakkar, Nadine; Wang, Jingxin; Ladner, Katherine J et al. (2008) IKK/NF-kappaB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis. J Cell Biol 180:787-802
Acharyya, Swarnali; Villalta, S Armando; Bakkar, Nadine et al. (2007) Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. J Clin Invest 117:889-901
Acharyya, Swarnali; Guttridge, Denis C (2007) Cancer cachexia signaling pathways continue to emerge yet much still points to the proteasome. Clin Cancer Res 13:1356-61
Acharyya, Swarnali; Butchbach, Matthew E R; Sahenk, Zarife et al. (2005) Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia. Cancer Cell 8:421-32
Acharyya, Swarnali; Ladner, Katherine J; Nelsen, Lori L et al. (2004) Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J Clin Invest 114:370-8