ORCID Profile
0000-0002-7286-046X
Current Organisation
University of Nottingham
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Publisher: Wiley
Date: 19-10-2023
DOI: 10.1113/JP285130
Publisher: Cold Spring Harbor Laboratory
Date: 11-12-2019
DOI: 10.1101/872127
Abstract: Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity, however, the mechanistic basis of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH) 2 D 3 ) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH) 2 D 3 to the regulation of skeletal muscle mitochondrial function in vitro , however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we utilised lentiviral mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared to shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P 0.001). VDR-KD myoblasts displayed a 30%, 30% and 36% reduction in basal, coupled and maximal respiration respectively ( P 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33% and 48% reduction in basal, coupled and maximal respiration ( P 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATP ox ) was reduced by 20% suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content as well as markers of fusion and fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro , providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Wiley
Date: 21-12-2020
DOI: 10.1002/JCSM.12661
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.CLNU.2018.06.963
Abstract: Age-related muscle loss (sarcopenia) may be driven by a diminished myofibrillar protein synthesis (MyoPS) response to anabolic stimuli (i.e. exercise and nutrition). Oral phosphatidic acid (PA) ingestion has been reported to stimulate resting muscle protein synthesis in rodents, and enhance resistance training-induced muscle remodelling in young humans. This study examined the effects of acute oral PA ingestion on resting and exercise-induced MyoPS rates in older in iduals. Sixteen older males performed a bout of unilateral leg resistance exercise followed by oral ingestion of 750 mg of soy-derived PA or a rice-flour placebo (PL) over 60 min post-exercise. A primed-continuous infusion of l-[ring- Plasma [PA] concentrations were elevated above basal values from 180 to 300 min post-exercise in PA only (P = 0.02). Exercise increased MyoPS rates above basal values between 150 and 300 min post-exercise in PL (P = 0.001), but not PA (P = 0.83). Phosphorylation of p70S6K, rpS6, 4E-BP1 and Akt was elevated above basal levels in the exercised leg over 150-300 min post-exercise for PL only (P = 0.018, 0.007, 0.011 and 0.002, respectively), and were significantly greater than PA (P < 0.01 for all proteins). The effects of oral PA ingestion on proteolytic signaling markers were equivocal. Acute oral phosphatidic acid ingestion appears to interfere with resistance exercise-induced intramuscular anabolic signaling and MyoPS in older males and, therefore, may not be a viable treatment to counteract sarcopenia. Clinicaltials.gov registration no: NCT03446924.
Publisher: BMJ
Date: 06-07-2018
DOI: 10.1136/THORAXJNL-2017-211073
Abstract: To characterise the sketetal muscle metabolic phenotype during early critical illness. Vastus lateralis muscle biopsies and serum s les (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5). From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (−27.4CN (95% CI −123.9 to 14.3) n=23 p=0.025) and mitochondrial DNA copy number (−1859CN (IQR −5557–1325) n=35 p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9) p .001) and decreased over 7 days (−4.8 mmol/kg dw (IQR −8.0–1.2) n=33 p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR −0.09–2.6) n=31 p .001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5–1672) n=15 p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR −0.44–3.33) n=29 p=0.041) and IL-10 (13.6 ng (IQR 3.4–39.0) n=29 p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7) p .001) and ghrelin (16.0 ng/mL (IQR −7–100) p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered. Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting. NCT01106300 .
Publisher: Springer Science and Business Media LLC
Date: 07-09-2015
Publisher: American Physiological Society
Date: 03-2020
DOI: 10.1152/AJPCELL.00568.2019
Abstract: Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH) 2 D 3 to the regulation of skeletal muscle mitochondrial function in vitro however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P 0.001). VDR-KD myoblasts displayed a 30%, 30%, and 36% reduction in basal, coupled, and maximal respiration, respectively ( P 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33%, and 48% reduction in basal, coupled, and maximal respiration ( P 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATP Ox ) was reduced by 20%, suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content, as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
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: Wiley
Date: 21-06-2016
DOI: 10.1111/APHA.12532
Publisher: Canadian Science Publishing
Date: 12-2015
Abstract: Skeletal muscle mass plays a vital role in locomotion, whole-body metabolic health, and is a positive predictor of longevity. It is well established the mammalian target of rapamycin (mTOR) is a central regulator of skeletal muscle protein turnover. The pursuit to find novel nutrient compounds or functional food sources that possess the ability to activate mTOR and promote skeletal muscle protein accretion has been on going. Over the last decade, a key role has been proposed for the phospholipid phosphatidic acid (PA) in mTOR activation. Mechanical load-induced (i.e., resistance exercise) intramuscular PA can directly bind to and activate mTOR. In addition, PA provided exogenously in cell culture heightens mTOR activity, albeit indirectly. Thus, endogenously generated PA and exogenous provision of PA appear to act through distinct mechanisms that converge on mTOR and, potentially, may lify muscle protein synthesis. In support of this notion, limited evidence from humans suggests that resistance exercise training combined with oral supplemental PA enhances strength gains and muscle hypertrophy. However, the precise mechanisms underpinning the augmented muscle remodelling response with supplemental PA remain elusive. In this review, we will critically examine available evidence from cell cultures and animal and human experimental models to provide an overview of the mechanisms through which endogenous and exogenous PA may act to promote muscle anabolism, and discuss the potential for PA as a therapeutic tool to maintain or restore skeletal muscle mass in the context of ageing and disease.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 03-2021
DOI: 10.14814/PHY2.14797
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2020
DOI: 10.1101/2020.05.15.098087
Abstract: Vitamin D deficiency is known to be associated with symptoms of skeletal muscle myopathy including muscle weakness and fatigue. Recently, vitamin D related metabolites have been linked to the maintenance of mitochondrial function within skeletal muscle. However, current evidence is limited to in vitro models and the effects of diet-induced vitamin D deficiency upon skeletal muscle mitochondrial function in vivo have received little attention. In order to examine the role of vitamin D in the maintenance of mitochondrial function in vivo , we utilised an established model of diet-induced vitamin D deficiency in C57BL/6J mice. Mice were fed either a control (2,200 IU/kg) or a vitamin D deplete (0 IU/kg) diet for periods of 1-, 2- and 3-months. Skeletal muscle mitochondrial function and ADP sensitivity were assessed via high-resolution respirometry and mitochondrial protein content via immunoblotting. As a result of 3-month of diet-induced vitamin D deficiency, respiration supported via CI+II P and ETC were 35% and 37% lower when compared to vitamin D replete mice ( P 0.05). Despite functional alterations, the protein expression of electron transfer chain subunits remained unchanged in response to dietary intervention ( P 0.05). In conclusion, we report that 3-months of diet-induced vitamin D deficiency reduced skeletal muscle mitochondrial function in C57BL/6J mice. Our data, when combined with previous in vitro observations, suggests that vitamin D mediated regulation of mitochondrial function may underlie the exacerbated muscle fatigue and performance deficits observed during vitamin D deficiency.
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 Philip Atherton.