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Precocious glucocorticoid exposure reduces skeletal muscle satellite cells in the fetal rat
Ganga Gokulakrishnan1,2, Xiaoyan Chang1, Ryan Fleischmann1
1USDA/ARS Children's Nutrition Research CenterDepartment of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Insights
Prenatal glucocorticoid exposure in rats reduces fetal muscle growth by impairing muscle progenitor cell proliferation and limiting satellite cell and myonuclear accretion. This contributes to reduced skeletal muscle development.
Area of Science:
- Developmental biology
- Muscle physiology
- Endocrinology
Background:
- Fetal skeletal muscle growth depends on protein and myonuclear addition.
- Prenatal glucocorticoid exposure (GLC) hinders fetal muscle growth, partly via reduced protein synthesis.
- The impact of GLC on myonuclear hyperplasia and muscle progenitor cells is not well understood.
Purpose of the Study:
- To investigate if glucocorticoids (GLC) impair fetal muscle growth by reducing Pax7+ muscle progenitor cell proliferation.
- To determine the effects of in utero dexamethasone exposure on fetal muscle growth, myonuclear accretion, and satellite cell activity.
Main Methods:
- Pregnant rats received dexamethasone (DEX) from embryonic day 13 to 21.
- Myonuclear accretion was assessed using bromodeoxyuridine (BrdU) labeling.
- Fetal muscle tissues were analyzed for fiber size, myonuclei number, progenitor cell markers (Pax7, MyoD), and myosin heavy chain isoforms.
Main Results:
- Dexamethasone exposure reduced mean fiber cross-sectional area (CSA), myonuclei per myofiber, and Pax7+ nuclei per myofiber.
- Myogenin abundance decreased, and slow myosin heavy chain increased in DEX-exposed fetuses.
- Reduced food intake in pair-fed controls explained smaller fiber CSA but not the effects on progenitor cell accretion.
Conclusions:
- Glucocorticoid exposure in utero inhibits fetal muscle progenitor cell proliferation, limiting satellite cell and myonuclear accretion.
- This reduction in progenitor cell activity and subsequent myonuclear number contributes to impaired fetal skeletal muscle growth.
- The findings highlight a novel mechanism by which prenatal glucocorticoids disrupt normal muscle development.
Abstract:
Perinatal skeletal muscle growth rates are a function of protein and myonuclear accretion. Precocious exposure of the fetus to glucocorticoids (GLC) in utero impairs muscle growth. Reduced muscle protein synthesis rates contribute to this response, but the consequences for myonuclear hyperplasia are unknown. To test the hypothesis that blunting of Pax7+ muscle progenitor cell proliferative activity by GLC in vivo also contributes to reduced fetal muscle growth, pregnant rats were administered dexamethasone (DEX: 1 mg/L drinking water) from embryonic day (ED) 13 to ED21. Their responses were compared to pair-fed (PF) and ad libitum-fed controls (CON). Bromodeoxyuridine (BrdU) was administered before delivery to measure myonuclear accretion. Fetal hind limb and diaphragm muscles were collected at term and analyzed for myofiber cross-sectional area (CSA), total and BrdU+ myonuclei, Pax7+ nuclei, MyoD and myogenin protein and mRNA abundance and myosin heavy chain (MyHC) isoform composition. Mean fiber CSA, myonuclei/myofiber and Pax7+ nuclei/myofiber ratios were reduced in DEX compared to those in CON and PF muscles; CSA/myonucleus, BrdU+/total myonuclei and BrdU+ myonuclei/Pax7+ nuclei were similar among groups. Myogenin abundance was reduced and MyHC-slow was increased in DEX fetuses. The data are consistent with GLC inhibition of muscle progenitor cell proliferation limiting satellite cell and myonuclear accretion. The response of PF-fed compared to CON muscles indicated that decreased food consumption by DEX dams contributed to the smaller myofiber CSA but did not affect Pax7+ nuclear accretion. Thus, the effect on satellite cell reserve and myonuclear number also contributes to the blunting of fetal muscle growth by GLC.
