TY - JOUR
T1 - Overexpression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy
AU - Bass, Joseph J.
AU - Nakhuda, Asif
AU - Deane, Colleen S.
AU - Brook, Matthew S.
AU - Wilkinson, Daniel J.
AU - Phillips, Bethan E.
AU - Philp, Andrew
AU - Tarum, Janelle
AU - Kadi, Fawzi
AU - Andersen, Ditte
AU - Garcia, Amadeo Munoz
AU - Smith, Ken
AU - Gallagher, Iain J.
AU - Szewczyk, Nathaniel J.
AU - Cleasby, Mark E.
AU - Atherton, Philip J.
N1 - Funding Information:
We would like to thank Professor Martin Hewison (Institute of Metabolism and Systems Research, University of Birmingham) for assistance on bioinformatic and pathway analysis. This work was supported by the Medical Research Council [grant number MR/J500495/1]. DJW was a post-doctoral research fellow funded through the MRC-ARUK Centre for Musculoskeletal Ageing Research awarded to the Universities of Nottingham and Birmingham. This work was supported by a grant from the Physiological Society (to PJA and KS).
Funding Information:
We would like to thank Professor Martin Hewison (Institute of Metabolism and Systems Research, University of Birmingham) for assistance on bioinformatic and pathway analysis. This work was supported by the Medical Research Council [grant number MR/J500495/1 ]. DJW was a post-doctoral research fellow funded through the MRC-ARUK Centre for Musculoskeletal Ageing Research awarded to the Universities of Nottingham and Birmingham . This work was supported by a grant from the Physiological Society (to PJA and KS).
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/12
Y1 - 2020/12
N2 - Objective: The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans.Methods: Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D2O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis.Results: Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.Conclusion: VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues. (C) 2020 The Author(s). Published by Elsevier GmbH.
AB - Objective: The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans.Methods: Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D2O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis.Results: Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.Conclusion: VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues. (C) 2020 The Author(s). Published by Elsevier GmbH.
KW - Exercise
KW - Metabolism
KW - Skeletal muscle
KW - Vitamin D
KW - PATHWAYS
KW - CAPACITY
KW - REGENERATION
KW - INCREASES
KW - STRENGTH
KW - INSULIN
KW - SUPPLEMENTATION
KW - CONTRACTION
KW - FOCAL ADHESION KINASE
KW - EXPRESSION
U2 - 10.1016/j.molmet.2020.101059
DO - 10.1016/j.molmet.2020.101059
M3 - Article
C2 - 32771696
SN - 2212-8778
VL - 42
JO - Molecular Metabolism
JF - Molecular Metabolism
M1 - 101059
ER -