Lithium Chloride Protects against Sepsis-Induced Skeletal Muscle Atrophy and Cancer Cachexia

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.

Global Lysine Acetylome Analysis of LPS-Stimulated HepG2 Cells Identified Hyperacetylation of PKM2 as a Metabolic Regulator in Sepsis

“…Based on the results from the KEGG analysis regarding the upregulated acetylome, the acetylation increased in four proteins-ALDOA, PGK1, ENO1, and PKM2-in the glycolysis pathways. The sepsis metabolism is associated with various metabolic changes, including insulin resistance, hyperlactatemia, hypoglutaminemia, hypercatabolism, and muscle wasting [33][34][35][36]. In particular, an increase in lactate concentration, a diagnostic marker in the early stages of sepsis, is thought to be a sign of acute organ dysfunction [37].…”

Inhibiting 5‐lipoxygenase prevents skeletal muscle atrophy by targeting organogenesis signalling and insulin‐like growth factor‐1

“…Myotubes were visualized by myosin heavy chain immunocytochemistry using the previously published protocol. 15 Myotubes were classified as myosin heavy chain positive cells containing more than four nuclei. Myotube diameter was obtained by measuring the midpoint of all visible myotubes within four microscopic images captured using the 10× magnification objective.…”

“…Blotting and antibody incubation were carried out following the previously published protocol. 15 Details of the primary and secondary antibodies are provided in Tables S1 and S2 , respectively.…”

Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia

“…2,200,201 Table 3 and Figure 2 summarize drugs under various clinical trials and their mechanisms. 91,92,100–102,174,199,202–219…”

“…2,200,201 Table 3 and Figure 2 summarize drugs under various clinical trials and their mechanisms. 91,92,100-102, 174,199,[202][203][204][205][206][207][208][209][210][211][212][213][214][215][216][217][218][219] ASCO guidelines recommend dietary assessment and psychological counseling as a crucial part of the treatment besides the drug-based treatments. 220 Artificial feeding with priority given to the enteral route has been the preferred way to treat terminally ill cancer patients.…”