Disrupted expression of genes essential for skeletal muscle fibre integrity and energy metabolism in Vitamin D deficient rats

Gogulothu, Ramesh; Nagar, Devika; Gopalakrishnan, Srividya; Garlapati, Venkat R.; Kallamadi, Prathap Reddy; Ismail, Azman

doi:10.1016/j.jsbmb.2019.105525

Cited by 27 publications

(16 citation statements)

References 45 publications

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“…Weaker anabolic signalling (via RPS6 and P70S6K) has been observed in response to vitamin D deficiency (18 weeks) (Gogulothu et al . 2020); however, this is probably due to systemic chronic responses to vitamin D deficiency. Interestingly, it was previously proposed that vitamin D deficiency induces muscle atrophy through greater proteasome‐mediated degradation (Bhat et al .…”

Section: Discussionmentioning

confidence: 99%

The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo

Bass

Kazi

Deane

et al. 2020

The Journal of Physiology

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Key points Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy. Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged. In response to VDR‐knockdown mitochondrial function and related gene‐set expression is impaired. In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation. These results highlight the autonomous role the VDR has within skeletal muscle mass regulation. Abstract Vitamin D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin D exerts its actions through the vitamin D receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down‐regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo, and myogenic regulation in vitro in C2C12 cells. Male Wistar rats underwent in vivo electrotransfer (IVE) to knock down the VDR in hind‐limb tibialis anterior (TA) muscle for 10 days. Comprehensive metabolic and physiological analysis was undertaken to define the influence loss of the VDR on muscle fibre composition, protein synthesis, anabolic and catabolic signalling, mitochondrial phenotype and gene expression. Finally, in vitro lentiviral transfection was used to induce sustained VDR‐KD in C2C12 cells to analyse myogenic regulation. Muscle VDR‐KD elicited atrophy through a reduction in total protein content, resulting in lower myofibre area. Activation of autophagic processes was observed, with no effect upon muscle protein synthesis or anabolic signalling. Furthermore, RNA‐sequencing analysis identified systematic down‐regulation of multiple mitochondrial respiration‐related protein and genesets. Finally, in vitro VDR‐knockdown impaired myogenesis (cell cycling, differentiation and myotube formation). Together, these data indicate a fundamental regulatory role of the VDR in the regulation of myogenesis and muscle mass, whereby it acts to maintain muscle mitochondrial function and limit autophagy.

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Section: Discussionmentioning

confidence: 99%

The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo

Bass

Kazi

Deane

et al. 2020

The Journal of Physiology

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“…While many studies of vitamin D deficiency and insufficiency focus on its impact on protein synthesis and degradation, there is also a growing body of evidence to suggest that vitamin D supplementation in deficient individuals improves measures of mitochondrial density and function (Sinha et al, 2013;Rana et al, 2014). These studies are supported by research in rodent models, where vitamin D supplementation in deficient animals improves the balance between muscle protein synthesis and degradation, as well as measures of mitochondrial density and function (Gogulothu et al, 2020).…”

Section: Vitamin D and Mitochondrial Healthmentioning

confidence: 99%

Vitamin D Promotes Skeletal Muscle Regeneration and Mitochondrial Health

et al. 2021

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Vitamin D is an essential nutrient for the maintenance of skeletal muscle and bone health. The vitamin D receptor (VDR) is present in muscle, as is CYP27B1, the enzyme that hydroxylates 25(OH)D to its active form, 1,25(OH)D. Furthermore, mounting evidence suggests that vitamin D may play an important role during muscle damage and regeneration. Muscle damage is characterized by compromised muscle fiber architecture, disruption of contractile protein integrity, and mitochondrial dysfunction. Muscle regeneration is a complex process that involves restoration of mitochondrial function and activation of satellite cells (SC), the resident skeletal muscle stem cells. VDR expression is strongly upregulated following injury, particularly in central nuclei and SCs in animal models of muscle injury. Mechanistic studies provide some insight into the possible role of vitamin D activity in injured muscle. In vitro and in vivo rodent studies show that vitamin D mitigates reactive oxygen species (ROS) production, augments antioxidant capacity, and prevents oxidative stress, a common antagonist in muscle damage. Additionally, VDR knockdown results in decreased mitochondrial oxidative capacity and ATP production, suggesting that vitamin D is crucial for mitochondrial oxidative phosphorylation capacity; an important driver of muscle regeneration. Vitamin D regulation of mitochondrial health may also have implications for SC activity and self-renewal capacity, which could further affect muscle regeneration. However, the optimal timing, form and dose of vitamin D, as well as the mechanism by which vitamin D contributes to maintenance and restoration of muscle strength following injury, have not been determined. More research is needed to determine mechanistic action of 1,25(OH)D on mitochondria and SCs, as well as how this action manifests following muscle injury in vivo. Moreover, standardization in vitamin D sufficiency cut-points, time-course study of the efficacy of vitamin D administration, and comparison of multiple analogs of vitamin D are necessary to elucidate the potential of vitamin D as a significant contributor to muscle regeneration following injury. Here we will review the contribution of vitamin D to skeletal muscle regeneration following injury.

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“…Bass et al demonstrated that overexpression of VDR in rats induced muscle hypertrophy, which was characterized by the increased muscle cross-sectional area, and that it enhanced anabolic signaling and translational efficacy, resulting in increased phosphorylated mTOR (p-mTOR) and downstream targets (p-4E-BP and p-p70S6K) [ 61 ]. Conversely, vitamin D deficiency in rats inhibited mTORC1 signaling and contributed to decreased protein synthesis in skeletal muscle [ 62 ]. These reports suggest that VDR in skeletal muscle plays important roles in muscle hypertrophy.…”

Section: Mechanism Of Action Of Vitamin D On Skeletal Musclementioning

confidence: 99%

Vitamin D and Sarcopenia: Potential of Vitamin D Supplementation in Sarcopenia Prevention and Treatment

2020

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Skeletal muscle, the largest organ in the human body, accounting for approximately 40% of body weight, plays important roles in exercise and energy expenditure. In the elderly, there is often a progressive decline in skeletal muscle mass and function, a condition known as sarcopenia, which can lead to bedridden conditions, wheelchair confinement as well as reducing the quality of life (QOL). In developed countries with aging populations, the prevention and management of sarcopenia are important for the improvement of health and life expectancy in these populations. Recently, vitamin D, a fat-soluble vitamin, has been attracting attention due to its importance in sarcopenia. This review will focus on the effects of vitamin D deficiency and supplementation on sarcopenia.

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Disrupted expression of genes essential for skeletal muscle fibre integrity and energy metabolism in Vitamin D deficient rats

Cited by 27 publications

References 45 publications

The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo

The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo

Vitamin D Promotes Skeletal Muscle Regeneration and Mitochondrial Health

Vitamin D and Sarcopenia: Potential of Vitamin D Supplementation in Sarcopenia Prevention and Treatment

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