Regulation of muscle growth by pathogen associated molecules

¹ Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033

^* To whom correspondence should be addressed. E-mail: rfrost{at}psu.edu.

	Abstract

Skeletal muscle demonstrates great plasticity in response to environmental and hormonal factors including pathogen-associated molecules, inflammatory cytokines, and growth factors. These signals impinge on muscle by forcing individual muscle fibers to either grow or atrophy. We recently demonstrated that skeletal muscle cells express multiple Toll-like receptors (TLR) that recognize bacterial cell wall components, such as lipopolysaccharide (LPS). Exposure of myocytes to LPS and other TLR ligands initiates an inflammatory response culminating in the autocrine production of cytokines and nitric oxide (NO) by nitric oxide synthase (NOS)2. The TLR signal through protein kinases that phosphorylate and promote the degradation of an inhibitory protein that normally retains the transcription factor, nuclear factor kappa B (NFB), in the cytoplasm. Phosphorylation and degradation of the inhibitor of NFB (IB) allows for translocation of NFB to the nucleus and activation of inflammatory genes. Overexpression of a constitutively active IB kinase in skeletal muscle causes severe wasting and we found that inhibitors of either the phosphorylation of IB or its proteolytic degradation prevent TLR ligand-induced expression of cytokines and NOS2. The combination of LPS and interferon (IFN) dramatically enhances the magnitude and duration of LPS-stimulated NOS2 expression and reduces protein translation. Lipopolysaccharide and IFN also down-regulates signaling from the mammalian target of rapamycin (mTOR), a kinase that directs changes in cell size. Inhibitors of NOS block the fall in muscle cell protein synthesis and restore translational signaling, indicating that activation of the NOS2-NO pathway is responsible for the observed decrease in muscle protein synthesis. Our work provides a molecular explanation for reduced muscle growth during infection. Muscle is largely self-sufficient because it expresses receptors, signaling pathways, and effectors to regulate its own size. Prolonged activation of NFB and NOS2 has emerged as detrimental facets of the immune response in muscle. The interplay between inflammatory components and growth factor signaling clearly places muscle at the interface between growth and immunity.

Key Words: Cytokines, endotoxin, growth, mammalian target of rapamycin, muscle, pathogens