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[A Cellular Pharmacological Approach to the Development of Drugs to Treat Muscle Wasting]

[A Cellular Pharmacological Approach to the Development of Drugs to Treat Muscle Wasting]

Kazuho Sakamoto

Yakugaku Zasshi. 2018;138(10):1271-1275.

PMID: 30270271

Abstract:

Skeletal muscle atrophy reduces quality of life and increases mortality. However, there are few available drugs for the treatment of muscle atrophy. Recently, cell signaling pathways involved in skeletal muscle atrophy or hypertrophy have been determined. To develop drugs for skeletal muscle atrophy, we have studied compounds which modulate pathways of myogenic differentiation, a pivotal step for the maintenance of skeletal muscle mass. First, we examined a K+ channel opener on myogenic differentiation, since hyperpolarization is a trigger for skeletal muscle differentiation. 5,6-Dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DCEBIO), an opener of the small/intermediate conductance Ca2+ activated K+ (SKCa/IKCa) channels, increases myogenic differentiation in C2C12 mouse skeletal myoblasts. This effect was inhibited by TRAM-34, an IKCa channel blocker. This suggests that K+ channels in skeletal muscle stem cells are potential targets for an anti-muscle atrophy drug. Next, we searched for drugs which prevent sepsis-induced muscle atrophy. Lipopolysaccharide (LPS), an inducer of sepsis, attenuates myogenic differentiation in C2C12 myoblasts. LPS also increases the protein expression of myostatin and activates NFκB during differentiation. The TLR4 signal inhibitor TAK-242, and an anti-TNFα neutralizing antibody, reduce these inflammatory responses. Our data suggest that LPS inhibits myogenic differentiation via the NFκB/TNFα pathway. This pathway may be involved in the development of muscle wasting caused by sepsis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP60563362	DCEBIO		60563-36-2	Price

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