Sepsis is a potentially fatal or life shortening syndrome due to infection induced systemic inflammatory responses. Numerous experimental and clinical studies indicate sex differences in sepsis. The outcome and survival rates from sepsis are better in women than in men. Morbidity due to sepsis is complicated by myopathy, and patients face longterm disability due to muscle atrophy and paralysis called intensive care unit acquired weakness (ICU-AW). Here, we examined the effects of estrogen on the septic inflammatory responses in skeletal muscle. 17β-estradiol (E2) attenuated muscle weakness induced by polymicrobial sepsis in ovariectomized mice. Furthermore, E2 attenuated atrophy, and inflammatory cytokine productions induced by lipopolysaccharide (LPS), an endotoxin in C2C12 myotubes. On the other hand, E2 did not change proteolysis pathways such as LPS induced atrogin-1/MAFbx upregulation and autophagosome formation in C2C12 myotubes. These findings indicate that E2 protects skeletal muscle from septic damage by reducing inflammatory cytokines. According to this study, estrogen should be one of the factors of sex difference in sepsis. Compounds with estrogen-like action may be potential seeds for drugs for ICU-AW treatment.
Skeletal muscle atrophy impairs quality of life. However, there is no effective medications. To maintain muscle mass, it is crucial to enhance differentiation of skeletal muscle stem cells and protein synthesis in myofibers. Our search using C2C12 cells determined that DCEBIO, a small/intermediate conductance Ca 2+ activated K + (SK/IK) channel opener promotes myogenic differentiation and muscle hypertrophy. DCEBIO hyperpolarized myoblast membrane potential and increased intracellular Ca 2+ concentration. The expression of myogenin was elevated. DCEBIO treatment increased phosphorylation level of S6K, but not that of Akt. DCEBIO did not alter the expression of atrophy and hypertrophy related genes. SK/IK channel blocker, apamin (100 nM) and TRAM-34 (1 μM) inhibited myogenic differentiation but did not attenuate hypertrophic effect of DCEBIO in C2C12 cells. These results suggest that DCEBIO enhances myogenic differentiation by opening of SK/IK channel and activating myogenic regulatory factor. In contrast, DCEBIO increases muscle mass by activating S6K independent of SK/IK channel activation. This is a significant study for future drug development for muscle atrophy.
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