Vitamin K2 Supplements for Muscle Recovery

Cachexia Clinical Trial

— Recovery  

Official title:

Effects of Vitamin K2 Supplements on Recovery of Lower Limb Muscle Function After Ankle Injury in Adults

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05161975
• Other study ID #: LithuanianSportsU-7
• Status: Not yet recruiting
• Phase: N/A
• Start date: December 15, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: November 2021
• Source: Lithuanian Sports University
• Contact: Aivaras Ratkevicius, Dr.
• Phone: +37069009974
• Email: aivaras.ratkevicius[@]lsu.lt
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Ankle injury is one of the most common injuries which can have long term consequences. Ankle immobilization is often applied for up to six weeks to ensure healing of the soft tissue and fractured bones after such an injury. This causes significant wasting of the lower leg muscles driven by inflammation and oxidative stress. The rate of muscle atrophy and recovery after injury varies significantly by sex and age. These differences might be linked to changes in gene and protein expression associated with regulation of protein synthesis and proteolysis. Interventions that reduce the deleterious effects of ankle injury as well as understanding of the underlying mechanisms could be particularly useful in promotion of healthy ageing. Vitamin K includes a group of structurally related compounds. Phylloquinone (vitamin K1) and menaquinones (vitamin K2s) of which MK-4 and MK-7 are the most important. Vitamin K2 has anti-inflammatory and antioxidant effects and thus may be effective in reducing muscle atrophy during limb immobilization and improving recovery of muscle function after injury. This aim of the current study is to investigate if vitamin K2 supplements can ameliorate muscle atrophy and improve recovery of muscle function after ankle injury. The investigators will study younger (18-39 year old) and older (40-60 year old) men and women to assess effects of sex and age.

Description:

Muscle weakness is associated with impaired quality of life, increased risk of falling, disability and premature mortality. Whilst ageing results in a progressive decline, even short periods of low physical activity can result in significant deterioration of muscle function and metabolic health. One such period of very low activity can occur following illness or injury. This can lead to decrease in lower limb muscle mass and strength. Muscle exercise training promotes recovery of skeletal muscles after injury though improvements vary between individuals and appear to decrease with age. Strategies to retard loss of muscle mass and function during inactivity are, thus, of critical importance in understanding of the mechanisms underlying such effects.

Vitamin K includes a group of structurally related compounds named phylloquinone (vitamin K1) and menaquinones (vitamin K2s) of which MK-4 and MK-7 are the most important. Vitamin K is an essential cofactor for gamma carboxylation, required for the effective function of a range of proteins and has been linked to chronic disease and inflammation. Muscle cell studies suggest that vitamin K2 increases expression of myogenic transcription factors such as MyoD and promotes muscle cell proliferation. There are 20 described vitamin K dependent proteins (VKDPs). It is also known that vitamin K2 inhibits the activation of NFkB independently of gamma-carboxylation. This prevents nuclear entry of NFkB and therefore, consequently, vitamin K2 inhibits NFkB to interact with its nuclear receptors. In addition, Vitamin K2 can function as an electron carrier in mitochondria, and therefore play an inhibitory role on oxidative stress and release of ROS. There is, therefore, a strong rationale for investigating the effects of vitamin K2 during ankle immobilisation. The aim of the study is to investigate the effects of vitamin K2 on skeletal muscles after ankle injury and in the recovery process.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: December 31, 2023
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• 18-60 years of age;

• Lives in Lithuania;

• Able and willing to give informed written consent to participate in the study;

• Recent (24 h before volunteering for the study) ankle injury requiring 6-week ankle immobilization;

• Exercise training program during 6-week recovery is recommended.

Exclusion Criteria:

• Body mass index (BMI) is greater than 30 kg / m2;

• Diabetes complicates cardiovascular diseases,

• Liver disease;

• Blood pressure is greater than 150/90mmHg during the first measurement;

• Incidences of consciousness loss;

• Cancer;

• Dementia;

• Other injuries that affect lower limb muscles;

• Use of anticoagulant drugs;

• Smoking;

• Drug abuse;

• Using drugs that affect muscle function (steroids).

Related Conditions & MeSH terms

• Cachexia
• Muscle Atrophy
• Muscular Atrophy

Intervention

Dietary Supplement:
• Vitamin K2
Volunteers will be randomly assigned to vitamin K2 or placebo group and consume one tablet of the food supplement per day.

Locations

Country	Name	City	State
Lithuania	Lithuanian Sports University	Kaunas
Lithuania	LSMU Kauno ligonine	Kaunas

Sponsors (3)

Lead Sponsor	Collaborator
Lithuanian Sports University	Kappa Bioscience AS, LSMU Kauno ligonine

Country where clinical trial is conducted

Lithuania, 

References & Publications (21)

Atherton PJ, Greenhaff PL, Phillips SM, Bodine SC, Adams CM, Lang CH. Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence. Am J Physiol Endocrinol Metab. 2016 Sep 1;311(3):E594-604. doi: 10.1152/ajpendo.00257.2016. Epub 2016 Jul 5. Review. — View Citation

Azuma K, Inoue S. Multiple Modes of Vitamin K Actions in Aging-Related Musculoskeletal Disorders. Int J Mol Sci. 2019 Jun 11;20(11). pii: E2844. doi: 10.3390/ijms20112844. Review. — View Citation

Celis-Morales CA, Welsh P, Lyall DM, Steell L, Petermann F, Anderson J, Iliodromiti S, Sillars A, Graham N, Mackay DF, Pell JP, Gill JMR, Sattar N, Gray SR. Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all cause mortality: prospective cohort study of half a million UK Biobank participants. BMJ. 2018 May 8;361:k1651. doi: 10.1136/bmj.k1651. — View Citation

Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan 1;48(1):16-31. doi: 10.1093/ageing/afy169. Erratum in: Age Ageing. 2019 Jul 1;48(4):601. — View Citation

Harshman SG, Shea MK. The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis. Curr Nutr Rep. 2016 Jun;5(2):90-98. Epub 2016 Mar 31. — View Citation

Haugsgjerd TR, Egeland GM, Nygård OK, Vinknes KJ, Sulo G, Lysne V, Igland J, Tell GS. Association of dietary vitamin K and risk of coronary heart disease in middle-age adults: the Hordaland Health Study Cohort. BMJ Open. 2020 May 21;10(5):e035953. doi: 10.1136/bmjopen-2019-035953. — View Citation

Hotamisligil GS. Foundations of Immunometabolism and Implications for Metabolic Health and Disease. Immunity. 2017 Sep 19;47(3):406-420. doi: 10.1016/j.immuni.2017.08.009. Review. — View Citation

Juto H, Nilsson H, Morberg P. Epidemiology of Adult Ankle Fractures: 1756 cases identified in Norrbotten County during 2009-2013 and classified according to AO/OTA. BMC Musculoskelet Disord. 2018 Dec 13;19(1):441. doi: 10.1186/s12891-018-2326-x. — View Citation

Krogh-Madsen R, Thyfault JP, Broholm C, Mortensen OH, Olsen RH, Mounier R, Plomgaard P, van Hall G, Booth FW, Pedersen BK. A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity. J Appl Physiol (1985). 2010 May;108(5):1034-40. doi: 10.1152/japplphysiol.00977.2009. Epub 2009 Dec 31. Erratum in: J Appl Physiol. 2010 May;108(5):1034. — View Citation

Laufs U, Wassmann S, Czech T, Münzel T, Eisenhauer M, Böhm M, Nickenig G. Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):809-14. Epub 2005 Feb 3. — View Citation

McGlory C, Gorissen SHM, Kamal M, Bahniwal R, Hector AJ, Baker SK, Chabowski A, Phillips SM. Omega-3 fatty acid supplementation attenuates skeletal muscle disuse atrophy during two weeks of unilateral leg immobilization in healthy young women. FASEB J. 2019 Mar;33(3):4586-4597. doi: 10.1096/fj.201801857RRR. Epub 2019 Jan 10. — View Citation

Meng SJ, Yu LJ. Oxidative stress, molecular inflammation and sarcopenia. Int J Mol Sci. 2010 Apr 12;11(4):1509-26. doi: 10.3390/ijms11041509. Review. — View Citation

Psatha M, Wu Z, Gammie F, Ratkevicius A, Wackerhage H, Redpath TW, Gilbert FJ, Meakin JR, Aspden RM. Age-related changes in the effects of strength training on lower leg muscles in healthy individuals measured using MRI. BMJ Open Sport Exerc Med. 2017 Jul 20;3(1):e000249. doi: 10.1136/bmjsem-2017-000249. eCollection 2017. — View Citation

Psatha M, Wu Z, Gammie FM, Ratkevicius A, Wackerhage H, Lee JH, Redpath TW, Gilbert FJ, Ashcroft GP, Meakin JR, Aspden RM. A longitudinal MRI study of muscle atrophy during lower leg immobilization following ankle fracture. J Magn Reson Imaging. 2012 Mar;35(3):686-95. doi: 10.1002/jmri.22864. Epub 2011 Nov 1. — View Citation

Rønning SB, Pedersen ME, Berg RS, Kirkhus B, Rødbotten R. Vitamin K2 improves proliferation and migration of bovine skeletal muscle cells in vitro. PLoS One. 2018 Apr 4;13(4):e0195432. doi: 10.1371/journal.pone.0195432. eCollection 2018. — View Citation

Rosa-Caldwell ME, Lim S, Haynie WS, Jansen LT, Westervelt LC, Amos MG, Washington TA, Greene NP. Altering aspects of mitochondrial quality to improve musculoskeletal outcomes in disuse atrophy. J Appl Physiol (1985). 2020 Dec 1;129(6):1290-1303. doi: 10.1152/japplphysiol.00407.2020. Epub 2020 Sep 17. — View Citation

Shearer MJ, Okano T. Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism. Annu Rev Nutr. 2018 Aug 21;38:127-151. doi: 10.1146/annurev-nutr-082117-051741. Epub 2018 Jun 1. Review. — View Citation

Simes DC, Viegas CSB, Araújo N, Marreiros C. Vitamin K as a Powerful Micronutrient in Aging and Age-Related Diseases: Pros and Cons from Clinical Studies. Int J Mol Sci. 2019 Aug 25;20(17). pii: E4150. doi: 10.3390/ijms20174150. Review. — View Citation

Sitnick M, Bodine SC, Rutledge JC. Chronic high fat feeding attenuates load-induced hypertrophy in mice. J Physiol. 2009 Dec 1;587(Pt 23):5753-65. doi: 10.1113/jphysiol.2009.180174. Epub 2009 Oct 12. — View Citation

Stevens JE, Pathare NC, Tillman SM, Scarborough MT, Gibbs CP, Shah P, Jayaraman A, Walter GA, Vandenborne K. Relative contributions of muscle activation and muscle size to plantarflexor torque during rehabilitation after immobilization. J Orthop Res. 2006 Aug;24(8):1729-36. — View Citation

Wolfe RR. The underappreciated role of muscle in health and disease. Am J Clin Nutr. 2006 Sep;84(3):475-82. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Muscle thickness	Transverse images of medial and lateral gastrocnemius, soleus and tibialis anterior muscles will be obtained using B-mode ultrasonography with a 10-15 MHz transducer.	12 weeks.
Primary	Muscle strength	Plantar flexor and extensor strength will be measured using isokinetic dynamometer (Biodex System 3 Biodex Medical Systems, Inc., Shirley, NY, USA).	12 weeks.
Primary	Vitamin K2 status	Blood samples will be taken and plasma levels of vitamin K2 will be assessed.	12 weeks.
Secondary	Cytokine profile	Blood samples will be taken and ELISA assays for insulin, myostatin, TGF-ß2, IGF-1, IL-1b, IL-6 and TNF-alpha will be performed	12 weeks.
Secondary	Gene expression profile	Biopsies of soleus and gastrocnemius muscles will be taken. The mRNA levels of p62, Atrogin 1, MuRF 1, LC3b and Gapdh were assessed using SYBR Green (#4367659, Thermo Fisher Scientific) assay for quantitative PCR.	12 weeks.
Secondary	Protein expression profile	Biopsies of soleus and gastrocnemius muscles will be taken. Western blotting will be carried to examine signalling pathways that control protein synthase (Akt-mTOR-p70s6k).	12 weeks.
Secondary	Metabolic enzyme activity	Biopsies of soleus and gastrocnemius muscles will be taken. Enzyme assays for citrate synthase (CS), succinate dehydrogenase (SDH), ß-hydroxyacyl-coenzyme dehydrogenase (HAD) and other metabolic enzyme will be carried out.	12 weeks.