Maternal vitamin D deficiency affects the morphology and function of glycolytic muscle in adult offspring rats

Reis, Natany Garcia; Assis, Ana Paula de; Lautherbach, Natália; Gonçalves, Dawit A. P.; Silveira, Wilian A.; Morgan, Henrique Jorge Novaes; Valentim, Rafael Rossi; Almeida, Lucas Ferreira de; Heck, Lilian C; Zanon, Neusa Maria; Koike, Tatiana Emy; Santos, Audrei R; Miyabara, Elen Haruka; Kettelhut, Ísis C.; Navegantes, Luiz Carlos Carvalho

doi:10.1002/jcsm.12986

Cited by 6 publications

(6 citation statements)

References 43 publications

(72 reference statements)

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“…Recent studies have shown that lack of vitamin D signalling leads to atrophy of type II muscle fibres 26,27 . The results presented here show that weaning vdr −/− mice on a milk‐based HFD alleviates defects in growth, muscle mass and glucose homeostasis.…”

Section: Discussionsupporting

confidence: 56%

“…Recent studies have shown that lack of vitamin D signalling leads to atrophy of type II muscle fibres. 26,27 The results presented here show that weaning vdr À/À mice on a milk-based HFD alleviates defects in growth, muscle mass and glucose homeostasis. The data show that the skeletal muscles in these mice are predisposed to utilize fatty acids as the primary energy source and accordingly exhibit an increase in the oxidative type I and type IIa fibres.…”

Section: Discussionmentioning

confidence: 67%

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Lack of vitamin D signalling shifts skeletal muscles towards oxidative metabolism

Das,

Jawla,

Meena

et al. 2023

J cachexia sarcopenia muscle

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BackgroundMice lacking vitamin D receptor (VDR) exhibit a glycogen storage disorder, disrupting carbohydrate utilization in muscle. Here, we asked if the defective carbohydrate metabolism alters the fat utilization by the skeletal muscles of vdr−/− mice.MethodsTo check the effect of high‐fat‐containing diets on muscle mass and metabolism of vdr−/− mice, we subjected them to two different milk fat‐based diets (milk fat diet with 60% of energy from milk fat and milk‐based diet [MBD] with 37% of energy from milk fat) and lard‐based high‐fat diet (HFD) containing 60% of energy from lard fat. Skeletal muscles and pancreas from these mice were analysed using RNA sequencing, quantitative reverse transcription polymerase chain reaction and western blot to understand the changes in signalling and metabolic pathways. Microscopic analyses of cryosections stained with haematoxylin and eosin, BODIPY, succinate dehydrogenase and periodic acid–Schiff reagent were performed to understand changes in morphology and metabolism of muscle fibres and pancreatic islets.ResultsTranscriptomic analyses showed that the skeletal muscles of vdr−/− mice exhibit upregulation of the fatty acid oxidation pathways, suggesting a shift towards increased lipid utilization even in a carbohydrate‐enriched regular chow diet (chow). Two different milk fat‐enriched diets restored body weight (12.01 ± 0.33 g in chow vs. 17.99 ± 0.62 g in MBD) and muscle weights (38.58 ± 3.84 mg in chow vs. 110.72 ± 1.96 mg in MBD for gastrocnemius [GAS]) of vdr−/− mice. Muscle ATP levels (0.56 ± 0.18 μmol in chow vs. 1.48 ± 0.08 μmol in MBD) and protein synthesis (0.25 ± 0.04 A.U. in chow vs. 2.02 ± 0.06 A.U. in MBD) were upregulated by MBD. However, despite increasing muscle energy levels, HFD failed to restore the muscle mass and cross‐sectional area to that of wild‐type (WT) mice (104.95 ± 2.6 mg for WT mice on chow vs. 77.26 ± 1.7 mg for vdr−/− mice on HFD for GAS). Moreover, HFD disrupted glucose homeostasis in vdr−/− mice, while MBD restored it. We further analysed insulin response and pancreatic insulin levels of these mice to show that HFD led to reduced insulin levels in pancreatic beta cells of vdr−/− mice (mean intensity of 1.5 × 10−8 for WT mice on chow vs. 4.3 × 10−9 for vdr−/− mice on HFD). At the same time, MBD restored glucose‐stimulated pancreatic insulin response (mean intensity of 9.2 × 10−9).ConclusionsSkeletal muscles of vdr−/− mice are predisposed to utilize fatty acids as their primary energy source to circumvent their defective carbohydrate utilization. Thus, HFDs could restore energy levels in the skeletal muscles of vdr−/− mice. This study reveals that when mice are subjected to a lard‐based HFD, VDR signalling is essential for maintaining insulin levels in pancreatic islets. Our data show a critical role of VDR in muscle metabolic flexibility and pancreatic insulin response.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 67%

Lack of vitamin D signalling shifts skeletal muscles towards oxidative metabolism

Das,

Jawla,

Meena

et al. 2023

J cachexia sarcopenia muscle

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“…Also, different types of muscle can be in uenced by different stimulation. For example, recent work demonstrated that only glycolytic muscles like extensor digitorum longus, rather than slow-twitch skeletal muscle, showed morphological and biochemical changes in male offspring of maternal vitamin D de ciency (24). In our work, we found composition in TA of oxidative myo bers was decreased, while glycolytic myo bers was increased by hyperglycemic exposure, demonstrated by mitochondrial malformation in soleus, inhibited oxidative genes reduction and poor-reacted insulin signaling pathway.…”

Section: Discussionsupporting

confidence: 52%

Intrauterine hyperglycemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling

Huang,

Yan,

2023

Preprint

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Background: Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates short-term intrauterine hyperglycemic environment for offspring, leading to insulin resistance in skeletal muscle, but the long-term effect and specific mechanism involved in skeletal muscle dysfunction in offspring remains to be clarified. Methods: Pregnant mice were divided into two groups: the GDM group was intraperitoneally injected with 100mg/kg streptozotocin on gestational days (GD) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose higher than 16.8mmol/L from GD13.5 will be regarded as GDM group. The growth of offspring was monitored and the glucose tolerance test was traced at different periods. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. Transmission electron microscopy was utilized to observe the morphology inside skeletal muscle at 8 weeks and fetus. Genes and protein expression associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also co-analyzed RNA sequencing and proteomics to explore its mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to explain the phenomenon. Results: Short-term intrauterine hyperglycemia inhibited the growth and reduced the lean mass of male offspring. The myofiber composition in GDM offspring male tibialis anterior muscle turned into glycolytic type. The morphology and function of mitochondria in skeletal muscle of GDM male offspring were destroyed, and co-analysis of RNA sequencing and proteomics of fetal skeletal muscle showed mitochondrial element and lipid oxidation were consistently impaired. Ex vivo and in vitro myoblast experiments also demonstrated that high glucose impeded mitochondrial organization and function, transcription of genes associated with mitochondrial biogenesis and oxidative metabolism was decrease at 8 weeks and fetal period. The protein and mRNA levels of Ppargc1a in male offspring were decreased at fetus (CTR vs GDM, 1.004 vs 0.665, p=0.002), 6 weeks (1.018 vs 0.511, p=0.023) and 8 weeks (1.006 vs 0.596, p=0.018) in skeletal muscle. In addition, CREB phosphorylation was restrained, with fewer activated pCREB protein binding to CRE element of Ppargc1a (1.042 vs 0.681, p=0.037), Pck(1.091 vs 0.432, p=0.014) and G6pc (1.118 vs 0.472, p=0.027), resulting in less transcription. Interestingly, we found sarcopenia and mitochondrial dysfunction could even be inherited by the next generation. Conclusions: Short-term intrauterine hyperglycemia reduced lean mass in male offspring significantly, and disrupted the organization and function of the mitochondrion in skeletal muscle which contributed to insulin resistance and glucose intolerance. Fetal exposure to hyperglycemia decreased phosphorylated CREB and reduced transcription of Ppargc1a. Abnormal mitochondrion was also observed in the F2 generation, which might be transmitted through aberrant gametes.

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“…Table 2 shows the summary of the risk of bias assessment. Seven of thirteen studies described random treatment in the allocation of the subject group [ 27 , 28 , 30 , 31 , 33 , 35 , 36 ]. No study has declared a blinding procedure in the intervention and outcome assessment.…”

Section: Resultsmentioning

confidence: 99%

“…In that study, maternal vitamin D deficiency selectively increased the number of satellite cells and myogenic regeneration factor in type 2 muscle fibers in adult male offspring. This finding may be due to an increase in local vitamin D production in adult age to compensate for the limited intrauterine vitamin D [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Effects of Vitamin D on Satellite Cells: A Systematic Review of In Vivo Studies

et al. 2022

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The non-classical role of vitamin D has been investigated in recent decades. One of which is related to its role in skeletal muscle. Satellite cells are skeletal muscle stem cells that play a pivotal role in skeletal muscle growth and regeneration. This systematic review aims to investigate the effect of vitamin D on satellite cells. A systematic search was performed in Scopus, MEDLINE, and Google Scholar. In vivo studies assessing the effect of vitamin D on satellite cells, published in English in the last ten years were included. Thirteen in vivo studies were analyzed in this review. Vitamin D increases the proliferation of satellite cells in the early life period. In acute muscle injury, vitamin D deficiency reduces satellite cells differentiation. However, administering high doses of vitamin D impairs skeletal muscle regeneration. Vitamin D may maintain satellite cell quiescence and prevent spontaneous differentiation in aging. Supplementation of vitamin D ameliorates decreased satellite cells’ function in chronic disease. Overall, evidence suggests that vitamin D affects satellite cells’ function in maintaining skeletal muscle homeostasis. Further research is needed to determine the most appropriate dose of vitamin D supplementation in a specific condition for the optimum satellite cells’ function.

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Maternal vitamin D deficiency affects the morphology and function of glycolytic muscle in adult offspring rats

Cited by 6 publications

References 43 publications

Lack of vitamin D signalling shifts skeletal muscles towards oxidative metabolism

Lack of vitamin D signalling shifts skeletal muscles towards oxidative metabolism

Intrauterine hyperglycemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling

Effects of Vitamin D on Satellite Cells: A Systematic Review of In Vivo Studies

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