Tumor necrosis factor-alpha (TNF-alpha) is suggested to promote atrophy and weakness of respiratory and limb skeletal muscles in diseases that range from chronic obstructive pulmonary disease to cancer, from congestive heart failure to AIDS. Despite its putative pathophysiological significance, surprisingly little is known about the mechanisms of TNF-alpha action in skeletal muscle. The long-term goal of this project is to determine the redox mechanisms by which TNF-alpha compromises muscle performance. Thus far, we have established that clinically-relevant levels of TNF-alpha act directly on skeletal muscle cells to stimulate loss of muscle protein without inducing apoptotic or necrotic cell death. Early signaling events in this catabolic response include activation of nuclear factor-kB (NFkB). Over several days, TNF-alpha/NFkB signaling accelerates degradation of muscle protein, causing a net protein loss. The current project extends our work on this pathway to address the underlying signaling events in greater depth and to evaluate the mechanism of accelerated protein degradation. We have three Specific Aims: 1.) To define receptor-mediated signaling events by which TNF-alpha activates NFkB in skeletal muscle. 2.) To evaluate regulation of ubiquitin conjugating activity by TNF-alpha. 3.) To evaluate the ubiquitin conjugating enzyme UbcH2 as an essential element of TNF-alpha/NFkB-regulated catabolism.
These aims will be addressed using an integrative approach that incorporates muscle preparations ranging from cultured myotubes to TNF-alpha treated animals. Cause/effect relationships will be evaluated using a panel of pharmacologic, immunologic, and genetic interventions. Results of the proposed studies will help establish molecular mechanisms whereby TNFalpha stimulates catabolism of respiratory and limb skeletal muscle.
| Li, Wei; Moylan, Jennifer S; Chambers, Melissa A et al. (2009) Interleukin-1 stimulates catabolism in C2C12 myotubes. Am J Physiol Cell Physiol 297:C706-14 |
| Moylan, Jennifer S; Smith, Jeffrey D; Chambers, Melissa A et al. (2008) TNF induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not AKT-Foxo1/3 signaling. Am J Physiol Cell Physiol 295:C986-93 |
| Hardin, Brian J; Campbell, Kenneth S; Smith, Jeffrey D et al. (2008) TNF-alpha acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle. J Appl Physiol 104:694-9 |
| Smith, Melissa A; Moylan, Jennifer S; Smith, Jeffrey D et al. (2007) IFN-gamma does not mimic the catabolic effects of TNF-alpha. Am J Physiol Cell Physiol 293:C1947-52 |
| Moylan, Jennifer S; Reid, Michael B (2007) Oxidative stress, chronic disease, and muscle wasting. Muscle Nerve 35:411-29 |
| Durham, William J; Arbogast, Sandrine; Gerken, Eric et al. (2006) Progressive nuclear factor-kappaB activation resistant to inhibition by contraction and curcumin in mdx mice. Muscle Nerve 34:298-303 |
| Smith, Melissa A; Reid, Michael B (2006) Redox modulation of contractile function in respiratory and limb skeletal muscle. Respir Physiol Neurobiol 151:229-41 |
| Gong, Ming C; Arbogast, Sandrine; Guo, Zhenheng et al. (2006) Calcium-independent phospholipase A2 modulates cytosolic oxidant activity and contractile function in murine skeletal muscle cells. J Appl Physiol 100:399-405 |
| Chen, Shuen-Ei; Gerken, Eric; Zhang, Yingmin et al. (2005) Role of TNF-{alpha} signaling in regeneration of cardiotoxin-injured muscle. Am J Physiol Cell Physiol 289:C1179-87 |
| Li, Yi-Ping; Chen, Yuling; John, Joseph et al. (2005) TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J 19:362-70 |
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