Related Experiment Video For 25-Hydroxycholesterol
Updated: May 17, 2025

An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
25-Hydroxycholesterol as a negative regulator of diaphragm muscle contractions via estrogen receptor and Ca2+
Eva A Kuznetsova1, Nikita S Fedorov1, Guzel F Zakyrjanova1,2
1Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan, 420111, Russia.
Abstract:
Cholesterol is involved in the regulation of various signaling processes, and oxysterols are essential lipid messengers. The cholesterol derivative 25-hydroxycholesterol (25-HC) is overproduced by muscle macrophages in sarcopenia, myasthenia, and neurodegenerative diseases. Herein, we examined the effects of 25-HC on Ca2+ signaling and contractions of the mouse diaphragm, the main respiratory muscle. We found that 25-HC increased resting levels of cytosolic Ca2+ in muscle fibers. This effect was dependent on estrogen receptor α (ERα) and was mediated by Ca2+-efflux from intracellular stores via dantrolene-insensitive and TMB-8-sensitive channels, presumably inositol trisphosphate receptors (IP3Rs). In addition, 25-HC suppressed diaphragm contractile responses to direct stimulation of the muscle fibers. The negative effect of 25-HC on contraction force was inhibited by blockers of ERα and Ca2+ mobilization. Thus, 25-HC may suppress diaphragm muscle contractility due to activation of an ERα/IP3R/Ca2+in axis in muscle fibers. At the same time, 25-HC did not significantly modify the contractions elicited by phrenic nerve stimulation and respiratory activity in vivo. We discuss that the previously found enhancement of neuromuscular transmission mediated by 25-HC in the diaphragm can compensate for the reduction in the muscle contractions in the case of phrenic nerve activation.
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