Abstract
Pregnancy promotes physiological adaptations throughout the body, mediated by the female sex hormones progesterone and estrogen. Changes in the metabolic properties of skeletal muscle enable the female body to cope with the physiological challenges of pregnancy and may also be linked to the development of insulin resistance. We conducted global microarray, proteomic, and metabolic analyses to study the role of the progesterone receptor and its transcriptional regulator, smoothelin-like protein 1 (SMTNL1) in the adaptation of skeletal muscle to pregnancy. We demonstrate that pregnancy promotes fiber-type changes from an oxidative to glycolytic isoform in skeletal muscle. This phenomenon is regulated through an interaction between SMTNL1 and progesterone receptor, which alters the expression of contractile and metabolic proteins. smtnl1(-/-) mice are metabolically less efficient and show impaired glucose tolerance. Pregnancy antagonizes these effects by inducing metabolic activity and increasing glucose tolerance. Our results suggest that SMTNL1 has a role in mediating the actions of steroid hormones to promote fiber switching in skeletal muscle during pregnancy. Our findings also bear on the management of gestational diabetes that develops as a complication of pregnancy in ~4% of women.
Highlights
Pregnancy promotes physiological adaptations throughout the body mediated by the female sex hormones
Detailed fiber typing of MHC isoform expression by immunohistochemistry (IHC) of Skeletal muscle (SKM) from non-pregnant wild type (WT) females showed that smoothelin-like protein 1 (SMTNL1) expression was confined only to type2a muscle fibers in murine plantaris muscle (Fig. 1E), which was confirmed in human SKM (Fig. 1G)
Data presented suggest that pregnancy hormones such as progesterone and estrogen trigger the switching of SKM to a glycolytic phenotype through their respective nuclear receptors (Fig. 6)
Summary
Pregnancy promotes physiological adaptations throughout the body mediated by the female sex hormones. We demonstrate that pregnancy promotes fiber-type changes from an oxidative to glycolytic isoform in skeletal muscle This phenomenon is regulated through an interaction between SMTNL1 and progesterone receptor, which alters the expression of contractile and metabolic proteins. SMTNL1 plays a major role in pregnancy to promote adaptive responses, and this process is mediated through interactions of SMTNL1 with the steroid hormone receptor PR-B. In vitro and in vivo SMTNL1 selectively binds PR and does not bind other steroid hormone receptors This suggests that SMTNL1 is a bifunctional co-regulator of PR-B signaling and provides a molecular mechanism whereby PR-B is targeted to alter gene expression patterns to coordinately promote alterations in uterine smooth muscle function during pregnancy [12]. We suggest that in SKM, these events are natural adaptations of normal pregnancy and potentially infer evolutionary advantages to the mother by increasing her ability to store fat and her physical strength to carry the developing fetus
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