ORCID Profile
0000-0001-8808-8243
Current Organisation
University of Nottingham
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Publisher: Wiley
Date: 19-10-2023
DOI: 10.1113/JP285130
Publisher: Wiley
Date: 24-12-2020
DOI: 10.1113/JP280652
Abstract: 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. 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.
Publisher: Elsevier BV
Date: 12-2020
Publisher: MDPI AG
Date: 17-12-2021
Abstract: Muscle deconditioning impairs both locomotor function and metabolic health, and is associated with reduced quality life and increased mortality rates. Despite an appreciation of the existence of phenomena such as muscle anabolic resistance, mitophagy, and insulin resistance with age and disease in humans, little is known about the mechanisms responsible for these negative traits. With the complexities surrounding these unknowns and the lack of progress to date in development of effective interventions, there is a need for alternative approaches. Metabolomics is the study of the full array of metabolites within cells or tissues, which collectively constitute the metabolome. As metabolomics allows for the assessment of the cellular metabolic state in response to physiological stimuli, any chronic change in the metabolome is likely to reflect adaptation in the physiological phenotype of an organism. This, therefore, provides a holistic and unbiased approach that could be applied to potentially uncover important novel facets in the pathophysiology of muscle decline in ageing and disease, as well as identifying prognostic markers of those at risk of decline. This review will aim to highlight the current knowledge and potential impact of metabolomics in the study of muscle mass loss and deconditioning in humans and will highlight key areas for future research.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Daniel James Wilkinson.