Clinical trial NCT06746389: Effects of Vitamin D Supplementation on Muscle Protein Synthesis
Official title: Effects of Vitamin D Supplementation on Myofibrillar Protein Synthesis Rates in Rested and Exercised Muscle in Young Adults: a Randomised, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Vitamin D Effects on MPS
Placebo Effects on MPS
Keywords: Muscle Protein Synthesis, Vitamin D, adults, healthy
Lead sponsor: University of Exeter
Sponsor class: OTHER
Collaborators: name: The University of Texas Medical Branch, Galveston
name: Wageningen University
First posted: 2024-12-24
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double Blind RCT
Primary purpose: TREATMENT

Brief summary: Background: Healthy adults maintain muscle tissue by continuously building up and breaking down muscle proteins throughout the day. Studies have shown that vitamin D (VitD) is essential for maintaining muscle mass by activating cellular pathways involved in building muscle via muscle protein synthesis (MPS). Although, various candidate molecules have been identified in animal models, it is not known whether these pathways are activated in humans. Interestingly, animal studies indicate that 20% of VitD is stored in human muscle cells, which may help maintain VitD sufficiency during winter in Northern latitudes when there is not much sunlight Objectives: We will investigate whether VitD supplementation increases the MPS response to feeding and exercise, VitD storage in muscle cells, and cellular pathways that are involved in healthy sedentary or moderately active adults.

Methods: Participants will consume either a placebo (sucrose) or the intervention (vitamin D3, 3000IU/day) for 12 weeks in a double-blinded randomised study. Before and after the intervention participants will have body composition measured. Blood and muscle samples will be taken before and after a bout of exercise and ingestion of 20 g protein in order to measure MPS.

Detailed description: Recent in vitro studies have demonstrated an anabolic role of vitamin D directly targeting skeletal muscle via vitamin D receptors (VDR) present in myotubes \[1,2,3\]. However, this has yet to be translated to in vivo human models.

25-hydroxyvitamin-D (25OHD) is the primary circulating metabolite and reference measurement for vitamin D status. This may then either be converted to 24,25-dihydroxyvitamin D3 (24,25OHD) to prevent intoxication \[4\] or be activated in the kidneys to 1,25-dihydroxyvitamin D (1,25OHD)\[5\].

Evidence support a biological role for 1,25OHD in skeletal muscle\[1-4,7\]. With focus on muscle hypertrophy, a study demonstrated that 25OHD can also be activated to 1,25OHD in myotubes\[8\] and promote cell proliferation, growth and differentiation of myocytes in in vitro skeletal muscle cells\[7,9-13\]. The mechanisms proposed include (i) gene expression of endocytic receptors for vitamin D binding protein (VDP) (megalin/cubulin) on the muscle cell surface membrane and (ii) high affinity for VDP to bind to actin inside the muscle cell. Furthermore, epidemiological studies support a positive role for vitamin D in human muscle function\[14-21\] and mechanistic studies implicate intracellular 25OHD in the regulation of protein metabolism. Cell culture and in vivo animal models demonstrate that 25OHD activates anabolic cell signalling proteins of the mTORC1 pathway in response to anabolic stimuli\[21,22\], which translates into an increased stimulation of muscle protein synthesis\[17\]. Despite these exciting results from cell culture and in vivo animal studies, no study has replicated these findings in in vivo human models.

The length of the intervention in studies investigating the effects of vitamin D supplementation on muscle health outcomes and MPS varies between studies; however, evidence supports improvements in fast-twitch muscle fibres in elderly women\[18\], muscle strength in humans and animals and an increased in MPS in rats and mice following a minimum of 12 weeks intervention \[22\]. Thus, this study plans to have 12 weeks of intervention to ensure there is sufficient time for a physiologically effect to take place. Seasonal variations in blood 25OHD concentrations have been evaluated in Caucasians residing in Northern Ireland\[4\]. Thirty-four percent were deficient (\<25nmol/L) in winter months\[4\]; however, despite insufficient sunlight in winter to synthesise vitamin D in skin, a significant proportion of a population resident in the same latitude, in Scotland, maintained blood 25OHD concentrations \>50nmol/L\[6\]. These data and a recent review\[8\] suggest that humans have evolved a storage mechanism, which allows 25OHD, produced in the summer, to be conserved and used more efficiently in winter.

Eligibility criteria: Inclusion Criteria:

* Healthy adults aged 18 - 45
* Sedentary and moderately active (NDNS)

Exclusion Criteria:

* Any diagnosed acute or chronic condition
* Very active (NDNS)
* On medication apart from contraceptive pill
* Not taking vitamin supplementation for 30 days before enrolling
* Not having been exposed to the sun (synthesising months - any country) in the previous 30 days

Primary outcomes:
measure: Fractional synthetic rate of amino acid incorporation into myofibrillar protein
timeFrame: 12 weeks x 4 time points
Secondary outcomes:
measure: Phosphorylated mTOR
timeFrame: 12 weeks x 4 time points
measure: Total mTOR
timeFrame: 12 weeks x 2 time points
measure: Plasma amino acid kinetics
timeFrame: 12 weeks x 16 time points
measure: Glucose
timeFrame: 12 weeks x 16 time points
measure: Insulin
timeFrame: 12 weeks x 14 time points
measure: Leg press
timeFrame: 12 weeks x 1 x1
measure: Leg extension
timeFrame: 12 weeks 1 x 1
Other outcomes:
Locations:
city: Exeter
country: United Kingdom
facility: University of Exeter
state: Devon
Study officials:
affiliation: University of Exeter
name: Raquel Revuelta Iniesta, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tieland M, Brouwer-Brolsma EM, Nienaber-Rousseau C, van Loon LJ, De Groot LC. Low vitamin D status is associated with reduced muscle mass and impaired physical performance in frail elderly people. Eur J Clin Nutr. 2013 Oct;67(10):1050-5. doi: 10.1038/ejcn.2013.144. Epub 2013 Aug 14.
citation: Vignale K, Greene ES, Caldas JV, England JA, Boonsinchai N, Sodsee P, Pollock ED, Dridi S, Coon CN. 25-Hydroxycholecalciferol Enhances Male Broiler Breast Meat Yield through the mTOR Pathway. J Nutr. 2015 May;145(5):855-63. doi: 10.3945/jn.114.207936. Epub 2015 Mar 18.
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citation: Montenegro KR, Cruzat V, Carlessi R, Newsholme P. Mechanisms of vitamin D action in skeletal muscle. Nutr Res Rev. 2019 Dec;32(2):192-204. doi: 10.1017/S0954422419000064. Epub 2019 Jun 17.
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citation: SANC. (2007) Update on Vitamin D: Position Statement by the Scientific Advisory Committee on Nutrition. London: TSO
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