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Muscle plasticity of male and female offspring rats in response to maternal vitamin D deficiency: from atrophy to compensatory muscle hypertrophy

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Author(s):
Natany Garcia Reis
Total Authors: 1
Document type: Doctoral Thesis
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Luiz Carlos Carvalho Navegantes; Lucila Leico Kagohara Elias; Anselmo Sigari Moriscot; Adriana Souza Torsoni
Advisor: Luiz Carlos Carvalho Navegantes
Abstract

The fetal stage is a critical window for skeletal muscle growth and development. However, little information is available about the impact of maternal vitamin D (Vit. D) deficiency (VDD) on the structure and function of skeletal muscle in offspring and its possible sexual dimorphic effects. Therefore, this work aimed to investigate the effects of maternal VDD, during pregnancy and lactation, on the morphology, metabolism, and contractile function of different skeletal muscles of male and female offspring rats, in childhood and adulthood. For this, rats (Wistar Hannover) were fed with a control diet (CTRL) (1000 UI of Vit. D3/kg of diet), VDD (0 UI of Vit. D3), or VDD+Ca (0 UI of Vit. D3 +2% Ca+1.25% P/kg of diet) for six weeks and during the periods of gestation and lactation. The supplemented group (VDD+Ca) was included to dissociate the effects of VDD from alterations in Ca+2 metabolism in the infant period. At weaning (21 days), male (M) and female (F) pups were separated into the following groups according to the maternal diet: M-CTRL and F-CTRL; M-VDD and F-VDD and M-VDD-Ca and F-VDD-Ca and euthanized. A part of the offspring of both sexes, CTRL and VDD, received a standard diet until 180 days. At 21 days, M-VDD and M-VDD-Ca weighed less than M-CTRL. This effect was associated with serum calcidiol and insulin reduction, adiposity reduction, muscle atrophy in extensor digitorum longus (EDL) and soleus, glycolytic and oxidative metabolism muscles, respectively, and hypoplasia in EDL. None of these changes were found in the female group. In EDL, muscle atrophy in the M-VDD group was accompanied by increased content and expression of Ca2+-dependent proteases (calpains) and atrogin-1. Maternal supplementation with Ca2+ did not prevent atrophy or increase calpains, but activated PKC, increased p25 content, a calpain cleavage product, inactivated the Insulin-IGF-1/Akt signaling pathway in EDL, and, interestingly, stimulated protein synthesis in EDL and soleus from male offspring. In the F-VDD and F-VDD-Ca groups, an increase in calpain content and a reduction in two negative muscle mass regulators (atrogin-1 and myostatin) were also observed. At 180 days, the animals showed increased adiposity, hyperinsulinemia, and reversal of muscle atrophy induced by VDD in the infant phase, with only the hypoplastic effect on EDL remaining. In parallel, there was an increase in the cross-sectional area of type IIB, IIA, and IIAX fibers and activation of the myogenic program indicated by the higher number of satellite cells and higher MyoD and myogenin content. In ex vivo functional studies, EDL from the M-VDD group became more resistant to fatigue and showed an increase in the phosphorylation status of the IGF-1/Insulin receptor and its downstream targets such as Ser473 Akt and Ser21/9 GSK-3β. In these muscles, maternal VDD induced a compensatory increase in calcitriol and CYP27B1 content, an enzyme that converts calcidiol to calcitriol. Most of these alterations were not observed in the soleus of the M-VDD group and EDL and soleus of female offspring. Taken together, these data show the importance of maternal Vit. D in the growth and muscle development of rats\' offspring varies according to the animal\'s age, fiber type, and sex. Furthermore, they indicate that glycolytic fibers trigger adaptive mechanisms to prolonged VDD. (AU)

FAPESP's process: 19/06517-1 - The effect of maternal vitamin D deficiency on offspring development and muscle protein metabolism
Grantee:Natany Garcia Reis
Support type: Scholarships in Brazil - Doctorate