lithium-chloride and Sepsis

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia.

Topics: Animals; Body Weight; Cachexia; Cell Differentiation; Cell Proliferation; Culture Media, Conditioned; Glycogen Synthase Kinase 3 beta; Inflammation; Lipopolysaccharides; Lithium Chloride; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Neoplasms; RAW 264.7 Cells; RNA, Small Interfering; Sepsis; SKP Cullin F-Box Protein Ligases; Tetrazolium Salts; Thiazoles

Sepsis is associated with muscle wasting, mainly reflecting increased muscle proteolysis. Recent studies suggest that inhibition of GSK-3beta activity may counteract catabolic stimuli in skeletal muscle. We tested the hypothesis that treatment of muscles from septic rats with the GSK-3beta inhibitors LiCl and TDZD-8 would reduce sepsis-induced muscle proteolysis. Because muscle wasting during sepsis is, at least in part, mediated by glucocorticoids, we also tested the effects of GSK-3beta inhibitors on protein degradation in dexamethasone-treated cultured myotubes. Treatment of incubated extensor digitorum longus muscles with LiCl or TDZD-8 reduced basal and sepsis-induced protein breakdown rates. When cultured myotubes were treated with LiCl or one of the GSK-3beta inhibitors SB216763 or SB415286, protein degradation was reduced. Treatment of incubated muscles or cultured myotubes with LiCl, but not the other GSK-3beta inhibitors, resulted in increased phosphorylation of GSK-3beta at Ser9, consistent with inactivation of the kinase and suggesting that the other inhibitors used in the present experiments inhibit GSK-3beta by phosphorylation-independent mechanisms. The present results suggest that GSK-3beta inhibitors may be used to prevent or treat sepsis-induced, glucocorticoid-regulated muscle proteolysis.

Topics: Animals; Cells, Cultured; Dexamethasone; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Lithium Chloride; Male; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; SKP Cullin F-Box Protein Ligases; Thiadiazoles; Tripartite Motif Proteins; Ubiquitin-Protein Ligases