Higher serum 25-hydroxy vitamin D (25(OH)D) concentrations are associated with improved cardiovascular outcomes(18), enhanced immune function(6), and a reduced incidence of cancer(15). Higher serum vitamin D concentrations have also been associated with greater muscle strength and performance in some (10,11,14,16,27,31,33) but not all (2,8,30) studies. Some studies measured single muscle group performance such as that measured by handgrip (8,14) or leg strength (10,11,16,27,31,33) and have been restricted to young (14,31) or elderly (11,16,33) subject groups. The present study measured 25(OH)D concentrations and tested strength in multiple muscle groups in 419 healthy adults as part of the Effects of STatins On skeletal Muscle function and Performance (STOMP) study (29) (R01HL081893). Muscle strength and vitamin D were compared to address the given discrepancies among previous research studies.
METHODS
Study sample
Data were obtained from healthy men and women enrolled in the STOMP study, a randomized double-blind clinical trial investigating the effect of atorvastatin 80 mg daily on skeletal muscle strength and exercise performance (29). The STOMP study was approved by the Hartford Hospital Institutional Review Board. Written informed consent was obtained from all participants. The STOMP population consisted of 205 men and 214 women, ≥20 yr old, recruited from study sites at Hartford Hospital, the University of Massachusetts-Amherst, and the University of Connecticut-Storrs. Baseline data for STOMP included anthropometrics, vital signs, serum 25(OH)D concentrations, and strength measurements, with the latter performed for 3 d before randomization to either statin or placebo. The first day of strength testing was designed for practice in the testing procedures and was not used in data analysis. Results from the second and third days of strength testing were averaged for each subject to minimize day-to-day variation.
Anthropometrics, vitals, and baseline activity levels
Weight was determined using a calibrated balance beam scale. Height was measured using a wall-mounted tape measure. Body mass index (BMI) was calculated by dividing the participants’ weight in kilograms by height in meters squared. Resting blood pressure was determined with a Welch Allyn floor sphygmomanometer after subjects were seated with their back supported for 5 min of rest and the arm positioned at heart level (7). Resting pulse was obtained using an electronic HR monitor. Participant’s physical activity was recorded for a 96-h period using an Actiwatch accelerometer (ActiGraph, Pensacola, FL). Physical activity was determined to control for variations in activity among subjects. Maximal oxygen uptake (V˙O2max) was determined after an 8- to 12-h fast using a modified Balke treadmill protocol (1) and breath-by-breath analysis of expired gases using a ParvoMedics TrueOne 2400 metabolic cart (ParvoMedics Corporation, Sandy, Utah).
Serum 25-OH vitamin D assay
Serum 25(OH)D was used to assess vitamin D status (4). Serum 25(OH)D was determined at the first baseline visit using an enzyme-linked immunosorbent assay (Clinical Laboratory Partners, Newington, CT). Serum samples were collected throughout the calendar year and classified as winter (December to February), spring (March to May), summer (June to August), and fall (September to November) samples (3) to account for possible seasonal variation in vitamin D levels (17).
Muscle strength and exercise performance assessment
Dominant hand isometric strength was measured using a calibrated Jamar hydraulic handgrip dynamometer (Lafayette Instrument Company, Lafayette, IN). Three maximal contractions lasting 3 s each with 1-min rest in between were recorded. An average of the three contractions was used as the criterion score. Dominant elbow flexion/extension and knee flexion/extension strength were measured with isometric and isokinetic testing protocols using a Biodex System 3 dynamometer (Biodex Medical, Shirley, NY). This system is a valid method for determining torque produced by these muscle groups (12). Participants warmed up by performing three submaximal contractions before each test. For the elbow isometric testing, subjects completed three maximal flexion and extension contractions with the elbow flexed at a 90° angle. After 5-min rest, participants performed elbow isokinetic testing consisting of four maximal contractions in succession at 1.05 rad·s−1 (60°·s−1). Participants rested for another 5 min before performing the same maneuver at 3.14 rad·s−1 (180°·s−1). Isometric knee testing was performed with the knee flexed at a 110° angle. Subjects performed three maximal flexion and extension contractions. After 5-min rest, participants performed isokinetic knee testing consisting of four maximal continuous contractions at 1.05 rad·s−1 (60°·s−1). They rested for another 5 min before performing four maximal continuous contractions at 3.14 rad·s−1 (180°·s−1). Average peak torque (APT) was calculated using the Biodex System 3 Software for all strength tests. Data between baseline visits 2 and 3 were averaged as the criterion score.
Statistical methods
The variable of interest was APT for each of the Biodex muscle tests and kilograms of force with handgrip. Strength variables and vitamin D were not normally distributed, so data were log transformed for analyses. For variables that were log transformed before modeling, the mean shown is the back-transformed mean of the log transform, and the dispersion is a coefficient of variation (%). Group differences in baseline characteristics between men and women were compared using one-way ANOVA. Univariate associations between vitamin D and strength were investigated using Pearson product–moment correlation coefficients. Relations between vitamin D and strength were determined with age and gender controlled for in the ANOVA model. If there was a significant effect of vitamin D on strength with age and gender included, the relative influence of other predictors was investigated using multiple linear regression to determine whether vitamin D remained significant and to determine the relative influence of each variable based on the partial correlation coefficient. The variables added to the model were resting HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, V˙O2max, physical activity counts, and season of vitamin D measurement. All two-way interactions between predictors were considered in multivariate models. Statistical significance was accepted at P ≤ 0.05. All analyses were performed using SPSS Statistics 15.0 (IBM Corporation, New York).
RESULTS
Data from 419 healthy adults were analyzed, of whom 214 (52%) were women (Table 1). In the present study, 1% of subjects had a serum vitamin D level less than 10 ng·dL−1, 7% had vitamin D levels between 10 and 20 ng·mL−1, 27% had vitamin D levels between 20 and 30 ng·mL−1, and 65% had a vitamin D level above 30 ng·mL−1. Age affected all baseline characteristics (P < 0.01 for all) except for resting HR, BMI, and physical activity counts. Season of phlebotomy was also significantly related to vitamin D status (both P < 0.001). There was a statistically significant difference between men and women for all mean strength values expressed as APT in newton-meters (N·m) (Table 2). Univariate correlations between serum 25(OH)D and the APT of the strength tests were not significant.
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TABLE 1: Subject characteristics (n = 419).
TABLE 2: Mean strength values (n = 419).
Relation between vitamin D and arm strength.
With age and gender included in the model, vitamin D was positively associated with six of seven arm strength measurements (Table 3). Handgrip was the only arm strength measurement that did not reach significance (P = 0.77). Vitamin D remained a significant predictor of arm strength even with multivariate analysis controlling for all other relevant baseline factors (Table 4).
TABLE 3: ANOVA results between vitamin D and strength for between-subject effects when age and gender were controlled (F-statistics/P value).
TABLE 4: Multivariate regression (partial correlation coefficients/
P values) for strength variables that were significantly associated with vitamin D from Table
3.
Relation between vitamin D and leg strength.
With age and gender included in the model, vitamin D was positively associated with four of six leg strength variables (Table 3), but most of these significant relations between vitamin D and lower body strength disappeared with multivariate analysis. Only two of the four remained significant in the multivariate analysis (Table 4).
DISCUSSION
This is to our knowledge the first large cross-sectional study investigating the relation between vitamin D status and arm and leg muscle strength in a wide age range of healthy adults. We have documented that higher vitamin D levels are associated with both arm and leg muscle strength after adjusting for age and gender. Only the association between arm isometric and isokinetic strength and vitamin D remains consistently positive, however, after controlling for confounders associated with muscle strength including HR, SBP, DBP, BMI, V˙O2max, physical activity counts, and season of phlebotomy. The association of serum 25(OH)D levels with leg strength was less robust, and only knee isometric strength remained significant in multivariate analyses.
There are few studies examining the relation between vitamin D status and muscle strength of the arms and hands. Serum 1,25(OH)2 vitamin D concentrations correlated directly with biceps force (P = 0.024) in a cohort of 211 elderly men between the ages of 71 and 86 yr (28). Serum 25(OH)D levels were also directly related to abduction (P = 0.001) and external rotation (P < 0.001) torque of shoulder muscles in men and women with rotator cuff disorders (22). Similarly, serum 25(OH)D was directly related to handgrip strength in 435 men (P = 0.004) and 541 women (P = 0.01) 65 yr or older (19) as well as among 70 women (P < 0.05) older than 65 yr whose 25(OH)D concentrations ranged from 8 to 20 ng·mL−1 (20). The rare study examining individuals across the adult age range has failed to observe a consistent relation between serum vitamin D and upper body strength, measured as handgrip (8). We observed a direct relation between 25(OH)D and upper arm strength in both men and women across the adult age range, suggesting that this effect of vitamin D is not limited to older subjects.
There are also few studies examining the relation between vitamin D status and leg muscle strength as determined by computerized dynamometer. Vitamin D levels less than 30 ng·mL−1 were associated with poor thigh isometric extension (P = 0.020) and flexion (P = 0.032) performance measured by Biodex testing in women 75 yr old (16). The present study also found a direct relation between 25(OH)D levels with isometric knee strength in both men and women over a broad age range (20 to 76 yr), but this relation did not persist when leg strength was tested in the isokinetic environment.
Vitamin D deficiency affects Type II skeletal muscle fibers and can produce a myopathy. Type II muscle fiber atrophy of the intercostals muscles has been reported in two cases of patients with osteomalacic myopathy and vitamin D levels less than 30 ng·mL−1 (32). Middle gluteal muscle samples from elderly women with vitamin D deficiency (<15.6 ng·mL−1) also show Type II muscle fiber atrophy compared with individuals with higher vitamin D levels (>15.6 ng·mL−1). Furthermore, when serum 25(OH)D levels were less than 15.6 ng·mL−1, the mean Type II fiber diameter correlated with vitamin D status (r = 0.714, P = 0.0011) (24). Similarly, when 1000 IU of vitamin D was provided daily for 2 yr to 96 elderly women with vitamin D deficiency (<10 ng·mL−1) in a randomized, placebo controlled trial, the Type II muscle fibers of the vastus lateralis in the vitamin D group increased an average of 96.5% in diameter, whereas the untreated group experienced a 22.5% decrease in diameter (P < 0.0001), and the diameter of Type II muscle fibers correlated with serum 25(OH)D concentrations (r = 0.558, P < 0.0001) (25). There was also a 59% reduction in falls with vitamin D supplementation in that study (25). Such results suggest that the effect of vitamin D may vary with the fiber type of the muscle but also suggest that vitamin D supplementation may have important clinical effects.
We observed stronger and more consistent associations between vitamin D levels and muscle strength in the arms than that in the legs. This observation agrees with the literature cited previously, but the explanation for this difference is unclear. Because serum 25(OH)D levels appear to affect Type II muscle fibers, differences in fiber type composition between the arms and legs could be responsible. In the rat, the biceps brachii are composed of 95% Type II fibers, whereas the vastus intermedius is composed of only 36% Type II fibers (9). There are few studies on fiber type distribution in humans. One study looked at fiber type distribution from 32 recent post-mortem humans and found that vastus intermedius was composed of 53% of Type II fibers, whereas the vastus lateralis was composed of 68% Type II fibers (13). This study only examined leg muscles and did not investigate differences between upper and lower body muscle groups. Alternatively, because the effects of vitamin D on skeletal muscle are mediated through the vitamin D receptor (VDR) (5), differences in VDR concentrations between different muscle groups could contribute to our observed differential effects between the arms and the legs, but we are unaware of studies examining differences in VDR expression in arm and leg muscles. Another explanation for the differential effect of vitamin D on upper and lower body strength may be attributable to a greater use of lower extremities during daily, load-bearing exercise, which thus increases modulation of leg strength by stimuli such as environment and lifestyle.
Another possible reason for the stronger association of 25(OH)D levels with the arms rather than the legs could be androgenic effects. Androgens are known to produce larger effects on the upper body musculature. Oxymetholone, an oral androgen, administered to older men increased upper body strength compared with placebo, but it did not significantly increase leg strength (26). Vitamin D supplementation increases serum testosterone levels in men. Middle aged men treated with 3332 IU of vitamin D increased total testosterone, biologically active testosterone, and free testosterone when compared with baseline over men treated with placebo (23). How vitamin D increases androgen levels is unclear, but it may decrease the aromatization of testosterone to estrogen. Vitamin D decreases aromatase mRNA expression in breast cancer cells, which would increase testosterone levels and decrease estrogen production, but increases aromatase gene expression in adrenocortical and prostate cancer cells. (21). We did not measure androgen levels in the present study so we cannot determine whether the effect on upper body strength was due to an interaction between vitamin D status and androgenic activity.
There are limitations to this study. We did not determine vitamin D intake via diet or supplementation so we cannot determine whether differences in vitamin D levels were due to sun exposure or oral intake. We did not measure other serum factors related to vitamin D metabolism including calcium, parathyroid hormone, phosphorus, and sex hormone levels so we cannot determine whether these could have contributed to the “vitamin D effect.” Despite these limitations, our results demonstrate that vitamin D levels are directly associated with both arm and leg muscle strength, although the later association only persisted during isometric testing and not isokinetic testing. These results suggest that vitamin D should be studied as a technique to maintain muscle strength and especially arm muscle strength in aging adults.
The authors wish to acknowledge the following individuals for their scientific contributions: Gualberto Ruano, M.D., Theodore Holford, Ph.D., JoAnne Foody, M.D., Pamela Hartigan, Ph.D., Ira Ockene, M.D., Stephanie Moeckel Cole, Ph.D., and Justin Keadle, B.S. The STOMP study is funded by NHLBI/National Institutes of Health grant RO1 HL081893 (P. Thompson).
Paul D. Thompson reports receiving research grants from the National Institutes of Health, GlaxoSmithKline, Anthera, B. Braun, Genomas, Roche, Aventis, Novartis, and Furiex; serving as a consultant for Astra Zenica, Furiex, Regeneron, Merck, Takeda, Roche, Genomas, Abbott, Lupin, Runners World, Genzyme, Sanolfi, Pfizer, and GlaxoSmithKline; receiving speaker honoraria from Merck, Pfizer, Abbott, Astra Zenica, GlaxoSmithKline, and Kowa; owing stock in Zoll, General Electric, JA Wiley Publishing, Zimmer, J&J, Sanolfi-Aventis, and Abbott; and serving as a medical legal consultant on cardiac complications of exercise, statin myopathy, tobacco, ezetimibe, and nonsteroidals. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
No relevant conflicts of interest are declared.
REFERENCES
1. American College of Sports Medicine. Thompson WR, Gordon NF, Pescatello LS.
ACSM’s Guidelines for Exercise Testing and Prescription. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2010, xxi, p. 380.
2. Annweiler C, Beauchet O, Berrut G, et al.. Is there an association between serum 25-hydroxyvitamin D concentration and muscle strength among older women? Results from baseline assessment of the EPIDOS study.
J Nutr Health Aging. 2009; 13 (2): 90–5.
3. Ardestani A, Parker B, Mathur S, et al.. Relation of vitamin D level to maximal oxygen uptake in adults.
Am J Cardiol. 2011; 107 (8): 1246–9.
4. Binkley N, Ramamurthy R, Krueger D. Low vitamin D status: definition, prevalence, consequences, and correction.
Endocrinol Metab Clin North Am. 2010; 39 (2): 287–301, table of contents.
5. Boland RL.
VDR activation of intracellular signaling pathways in skeletal muscle.
Mol Cell Endocrinol. 2011; 347: 11–6.
6. Borges MC, Martini LA, Rogero MM. Current perspectives on vitamin D, immune system, and chronic diseases.
Nutrition. 2011; 27 (4): 399–404.
7. Cecil RL, Goldman L, Schafer AI.
Goldman’s Cecil Medicine. 24th ed. Philadelphia: Elsevier/Saunders/; 2011, p. 376.
8. Ceglia L, Chiu GR, Harris SS, Araujo AB. Serum 25-hydroxyvitamin D concentration and physical function in adult men.
Clin Endocrinol (Oxf). 2011; 74 (3): 370–6.
9. Delp MD, Duan C. Composition and size of type I, IIA, IID/X, and IIB fibers and citrate synthase activity of rat muscle.
J Appl Physiol. 1996; 80 (1): 261–70.
10. Dhesi JK, Jackson SH, Bearne LM, et al.. Vitamin D supplementation improves neuromuscular function in older people who fall.
Age Ageing. 2004; 33 (6): 589–95.
11. Dretakis OE, Tsatsanis C, Fyrgadis A, et al.. Correlation between serum 25-hydroxyvitamin D levels and quadriceps muscle strength in elderly cretans.
J Int Med Res. 2010; 38 (5): 1824–34.
12. Drouin JM, Valovich-mcLeod TC, Shultz SJ, Gansneder BM, Perrin DH. Reliability and validity of the Biodex system 3 pro isokinetic dynamometer velocity, torque and position measurements.
Eur J Appl Physiol. 2004; 91 (1): 22–9.
13. Edgerton VR, Smith JL, Simpson DR. Muscle fibre type populations of human leg muscles.
Histochem J. 1975; 7 (3): 259–66.
14. Foo LH, Zhang Q, Zhu K, et al.. Low vitamin D status has an adverse influence on bone mass, bone turnover, and muscle strength in Chinese adolescent girls.
J Nutr. 2009; 139 (5): 1002–7.
15. Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: global perspective.
Ann Epidemiol. 2009; 19 (7): 468–83.
16. Gerdhem P, Ringsberg KA, Obrant KJ, Akesson K. Association between
25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women.
Osteoporos Int. 2005; 16 (11): 1425–31.
17. Guillemant J, Cabrol S, Allemandou A, Peres G, Guillemant S. Vitamin D–dependent seasonal variation of PTH in growing male adolescents.
Bone. 1995; 17 (6): 513–6.
18. Hosseinpanah F, Yarjanli M, Sheikholeslami F, Heibatollahi M, Eskandary PS, Azizi F. Associations between vitamin D and cardiovascular outcomes; Tehran Lipid and Glucose Study.
Atherosclerosis. 2011; 218 (1): 238–42.
19. Houston DK, Cesari M, Ferrucci L, et al.. Association between vitamin D status and physical performance: the InCHIANTI study.
J Gerontol A Biol Sci Med Sci. 2007; 62 (4): 440–6.
20. Janssen HC, Samson MM, Verhaar HJ. Muscle strength and mobility in vitamin D–insufficient female geriatric patients: a randomized controlled trial on vitamin D and calcium supplementation.
Aging Clin Exp Res. 2010; 22 (1): 78–84.
21. Lundqvist J, Norlin M, Wikvall K. 1alpha,25-dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and
androgen metabolism.
Biochim Biophys Acta. 2011; 1811 (4): 263–70.
22. Oh JH, Kim SH, Kim JH, Shin YH, Yoon JP, Oh CH. The level of vitamin D in the serum correlates with fatty degeneration of the muscles of the rotator cuff.
J Bone Joint Surg Br. 2009; 91 (12): 1587–93.
23. Pilz S, Frisch S, Koertke H, et al.. Effect of vitamin D supplementation on testosterone levels in men.
Horm Metab Res. 2011; 43 (3): 223–5.
24. Sato Y, Inose M, Higuchi I, Higuchi F, Kondo I. Changes in the supporting muscles of the fractured hip in elderly women.
Bone. 2002; 30 (1): 325–30.
25. Sato Y, Iwamoto J, Kanoko T, Satoh K. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial.
Cerebrovasc Dis. 2005; 20 (3): 187–92.
26. Schroeder ET, Singh A, Bhasin S, et al.. Effects of an oral
androgen on muscle and metabolism in older, community-dwelling men.
Am J Physiol Endocrinol Metab. 2003; 284 (1): E120–8.
27. Scott D, Blizzard L, Fell J, Ding C, Winzenberg T, Jones G. A prospective study of the associations between 25-hydroxy-vitamin D, sarcopenia progression and physical activity in older adults.
Clin Endocrinol (Oxf). 2010; 73 (5): 581–7.
28. Taes YE, Goemaere S, Huang G, et al.. Vitamin D binding protein, bone status and body composition in community-dwelling elderly men.
Bone. 2006; 38 (5): 701–7.
29. Thompson PD, Parker BA, Clarkson PM, et al.. A randomized clinical trial to assess the effect of statins on skeletal muscle function and performance: rationale and study design.
Prev Cardiol. 2010; 13 (3): 104–11.
30. Verreault R, Semba RD, Volpato S, Ferrucci L, Fried LP, Guralnik JM. Low serum vitamin d does not predict new disability or loss of muscle strength in older women.
J Am Geriatr Soc. 2002; 50 (5): 912–7.
31. Ward KA, Das G, Berry JL, et al.. Vitamin D status and muscle function in post-menarchal adolescent girls.
J Clin Endocrinol Metab. 2009; 94 (2): 559–63.
32. Yoshikawa S, Nakamura T, Tanabe H, Imamura T. Osteomalacic myopathy.
Endocrinol Jpn. 1979; 26 (Suppl): 65–72.
33. Zhu K, Austin N, Devine A, Bruce D, Prince RL. A randomized controlled trial of the effects of vitamin D on muscle strength and mobility in older women with vitamin D insufficiency.
J Am Geriatr Soc. 2010; 58 (11): 2063–8.
