Abstract
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.
Highlights
Inflammation-associated skeletal muscle wasting involves the activation of the transcriptional complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)via increase in circulating cytokines, such as interleukin-1β (IL-1β) [1]
Prior to evaluating the effect of Lithium chloride (LiCl) on cancer cachexia, we verified the effect of LiCl on myogenic differentiation
Inflammation-associated skeletal muscle wasting occurs in cancer cachexia and sepsisinduced skeletal muscle atrophy and significantly affects patient morbidity and mortality
Summary
Inflammation-associated skeletal muscle wasting involves the activation of the transcriptional complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)via increase in circulating cytokines, such as interleukin-1β (IL-1β) [1]. Cancer cachexia and intensive care unit-acquired weakness (ICUAW) produced by sepsis are two prominent examples of inflammation-associated skeletal muscle wasting [1,2,3]. Both conditions result from acute-phase responses and systemic inflammation [4,5]. Cancer cachexia affects approximately 50% of all cancer patients and can be an immediate cause of death by increasing the side effects of chemotherapy [6]. ICUAW occurs in approximately 90% of patients with severe sepsis and increases morbidity and mortality [7]. The development of effective therapeutics for inflammation-associated muscle wasting is a research priority
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