Abstract
Background
Myostatin is a negative regulator of muscle growth but the relationship between serum myostatin levels and muscle mass is unclear. This study investigated the association between serum myostatin levels and skeletal muscle mass among healthy older community residents in Taiwan, to evaluate the potential of serum myostatin as a biomarker for diagnosing sarcopenia and/or evaluating the effect of its treatment.
Methods
Study data were excerpted from a random subsample of the I‐Lan Longitudinal Aging Study population. Serum myostatin levels were determined and categorized into tertiles (low, medium, high). Relative appendicular skeletal muscle mass (RASM) was calculated as appendicular lean body mass by dual‐energy X‐ray absorptiometry divided by height squared (kg/m2). Low muscle mass was defined as recommended by the Asian Working Group for Sarcopenia.
Results
The analytic study sample comprised 463 adults (mean age: 69.1 years; 49.5% men). Compared with subjects with normal RASM, those with lower RASM were older and frailer, with significantly higher prevalence of malnutrition, lower serum dehydroepiandrosterone (DHEA) levels, and were more likely to have low serum myostatin status. Multivariable logistic regression analysis showed that male sex (OR 3.60, 95% CI 1.30–9.92), malnutrition (OR 4.39, 95% CI 1.56–12.36), DHEA (OR 0.99, 95% CI 0.99–1.00), and low myostatin (OR 3.23, 95% CI 1.49–7.01) were all independent risk factors for low RASM (all P < 0.05). In men, DHEA (OR 0.99, 95% CI 0.98–1.00) and low myostatin (OR 4.89, 95% CI 1.79–13.37) were significantly associated with low RASM (both P < 0.05); however, only malnutrition was associated with low RASM in women (OR 13.59, 95% CI 2.22–83.25, P < 0.05).
Conclusions
Among healthy community‐living older adults, low serum myostatin levels were associated with low skeletal muscle mass in men, but not in women. Our results do not support using serum myostatin levels to diagnose sarcopenia, or to monitor how it responds to treatments. Further research is needed to understand why men apparently differ from women in the interrelationship between their myostatin levels and muscle mass.
Keywords: Frailty, Sex, Myostatin, Sarcopenia, Skeletal muscle mass
Introduction
An important characteristic of aging is temporal changes in body composition between bone, muscle, and fat mass. From age 30, people may lose skeletal muscle mass at 3–8% per decade and at a considerably accelerated rate as they become older.1, 2 Loss of muscle mass may also lead to diminished muscle strength and physical performance, which heighten the risk of gait unsteadiness and falls, functional impairment, disability, and mortality3, 4, 5, 6; the contemporary definition of sarcopenia encompasses the aforementioned clinical characteristics. The aetiology and pathophysiology of sarcopenia are complex and multifactorial, involving physical inactivity, nutritional status, loss of muscle fibres and motor units, and hormonal changes, among others.7 The balance between myostatin, activin, and follistatin in the sarcopenia nexus has garnered extensive research interest, and several potential pharmacotherapeutic agents based on the action of myostatin have been developed.
The growth/differentiation factor 8 gene (GDF8) was discovered in 19978; its product, myostatin, is a member of the transforming growth factor‐beta superfamily that is secreted primarily by myocytes in skeletal muscle, and was the first negative regulator of skeletal muscle growth to be identified.8, 9, 10, 11 Knockout mice had muscular hypertrophy due to increased numbers of myocytes, myofiber size, and overall muscle size8 and rats with lower myostatin levels had accelerated myogenesis,11 whereas transgenic mice with higher serum myostatin had cachexia.10 Congruently, a child with a GDF8 loss‐of‐function mutation had significant muscle hypertrophy.12
Given its action on skeletal muscle, serum levels of myostatin have hypothetical potential as a biomarker for sarcopenia.13 However, the results of studies evaluating the relationship between serum myostatin and skeletal muscle mass are inconsistent, besides mostly deriving from subjects with particular diseases rather than healthy individuals. Inverse correlations between serum myostatin‐immunoreactive protein concentration and height‐corrected fat‐free mass and muscle mass suggest that myostatin may be a biomarker of age‐associated sarcopenia.13 Serum myostatin was also negatively associated with skeletal muscle mass in male patients with chronic obstructive pulmonary disease (COPD).14 Conversely, decreased plasma myostatin levels in heart‐failure patients with cachexia suggest that lower myostatin may prevent loss of skeletal muscle and progression of cachexia.15 Besides these inconsistencies, little is known about the relationship between serum myostatin and skeletal muscle mass among healthy individuals. Therefore, we investigated the association between serum myostatin and skeletal muscle mass among healthy older community residents.
Methods
Study design and subjects
Study subjects were a random subsample of the I‐Lan Longitudinal Aging Study (ILAS), which is a population‐based research cohort of 1839 adults aged 53–92 years, residing in I‐Lan (Yilan) County, Taiwan, who were randomly sampled through household registration records; individuals were invited to participate via mail or telephone and those who accepted were enrolled after giving written informed consent. ILAS excluded subjects who (i) were unable to cooperate or communicate with study investigators; (ii) declined or were unable to grant consent; (iii) were currently institutionalized; (iv) were known to have active diseases (cancer, sepsis, heart failure, COPD, etc.) or functional dependence, or had life‐expectancy <6 months; and (v) were planning to leave Yilan County.
This study analysed serum myostatin, activin, and follistatin measurements taken from a random subsample of 463 ILAS subjects. The Institutional Review Boards of National Yang Ming University and Taipei Veterans General Hospital approved the study protocol.
Demographic characteristics and laboratory data
Research nurses collected participants' demographic and medical details and took anthropometric measurements. Alcohol consumption was categorized as drinking or non‐drinking, and tobacco usage as currently smoking or non‐smoking.
All participants gave peripheral blood samples at 7–9 AM, after a 10 h overnight fast. Biochemistry measurements included serum albumin, alanine aminotransferase, uric acid, total cholesterol, serum creatinine, high‐sensitivity C‐reactive protein, homocysteine, testosterone, insulin‐like growth factor‐1, dehydroepiandrosterone (DHEA), and vitamin D3. The homeostasis model assessment of insulin resistance index was calculated for insulin resistance. Serum levels of myostatin, activin, and follistatin were measured by sandwich enzyme immunoassay kits (R&D systems, Inc., Minneapolis, USA). Low serum myostatin was defined as the lower tertile of subjects' collective serum myostatin levels.
Functional assessment and physical performance
Research nurses performed comprehensive functional assessments for all participants. Nutrition status was evaluated by Mini Nutritional Assessment,16 and cognitive impairment defined by a Mini‐Mental State Examination score <24.17 Mood was evaluated by the five‐item geriatric depression scale, with the five‐item geriatric depression scale ≥2 denoting depressive symptoms.18 Physical activity was assessed by International Physical Activity Questionnaire,19 the severity of underlying medical conditions by the Charlson Comorbidity Index,20 and frailty status was determined according to the Fried criteria, which comprise weight loss, physical inactivity, weakness, slowness, and exhaustion21; frailty was defined as having ≥3 items and pre‐frailty was defined as 1 or 2 items—those who met no Fried criteria were considered robust. Gait speed was measured by a timed 6 m walk at the participant's usual pace, and handgrip strength of the dominant hand in an upright position was measured with a digital dynamometer (Smedlay's Dynamo Meter; TTM, Tokyo, Japan).
Body composition
Total fat mass, fat‐free lean body mass, and bone mineral density were calculated from whole‐body dual‐energy X‐ray absorptiometry scan data. Appendicular skeletal mass was defined as the total fat‐free lean body mass from four limbs, and the relative appendicular skeletal muscle mass index (RASM) was derived from appendicular skeletal mass divided by height squared (kg/m2). Total body fat percentage was calculated as total fat mass divided by total body mass times 100.
Diagnosis of sarcopenia and related measurements
This study defined sarcopenia, according to recommendations by the Asian Working Group for Sarcopenia (AWGS),22 as low muscle mass plus low muscle strength and/or low physical performance; the respective cut‐off values were RASM: 7.0 kg/m2 for men and 5.4 kg/m2 for women based on dual‐energy X‐ray absorptiometry; handgrip strength: < 26 kg for men and <18 kg for women; gait speed: less than 0.8 m/s.
Statistical analysis
Categorical variables are expressed by percentage, and continuous data as mean plus/minus standard deviation. Categorical variables were compared by Chi‐square test, and continuous variables by Student's t‐test, as appropriate. Multivariate logistic regression was used to determine independent risk factors of RASM below the AWGS lower reference limit compared with normal RASM, by entering all variables with P < 0.1 in univariate analysis as covariates. All statistical analyses were performed using SPSS Statistics Version 18.0 for Microsoft Windows XP (SPSS Inc., Chicago, IL, USA). A two‐tailed P‐value of <0.05 was considered statistically significant.
Results
The 463 enrolled subjects had mean age of 69.1 ± 9.2 years and 49.5% were men. Based on the AWGS cut‐offs, 54 subjects (11.7%) had low RASM; however, the overall prevalence of sarcopenia was low, only 4.1% overall. Table 1 summarizes the functional, cognitive and clinical characteristics, and health behaviour of groups with low RASM and normal RASM. Low RASM was significantly more prevalent in men than in women, and men with low RASM had a significantly lower total body fat percentage than those with normal RASM. Compared with participants with normal RASM, the group with low RASM had lower mean body mass index, and had a higher proportion who were current smokers, and a lower proportion who consumed alcohol. Among the functional domains, a significantly higher proportion of subjects with low RASM were malnourished, but there were no significant differences in cognitive function, depressive symptoms, or walking speed.
Table 1.
Demographic characteristics of subjects with low vs. normal relative appendicular skeletal muscle mass
Data show number (%) or mean ± standard deviation | Relative appendicular skeletal muscle mass | ||
---|---|---|---|
Low (n = 54) | Normal (n = 409) | P‐value | |
Demographic & health‐related lifestyle factors | |||
Age (years) | 73.0 ± 9.6 | 68.6 ± 9.0 | <0.001 |
Sex | <0.001 | ||
Male | 38 (13.0) | 191 (86.9) | |
Female | 16 (6.8) | 218 (93.2) | |
Education (>6 years) | 11 (20.4) | 76 (18.6) | 0.75 |
Body mass index (kg/m2) | |||
Male | 22.3 ± 5.2 | 25.3 ± 3.1 | <0.001 |
Female | 21.2 ± 2.8 | 24.9 ± 3.5 | <0.001 |
Total body fat (%) | 27.3 ± 9.6 | 31.6 ± 8.1 | <0.001 |
Male | 23.4 ± 7.6 | 26.0 ± 6.1 | 0.021 |
Female | 36.5 ± 7.5 | 36.4 ± 6.3 | 0.991 |
Smoking | 30 (55.6) | 140 (34.2) | <0.001 |
Alcohol drinking | 165 (40.3) | 29 (53.7) | 0.040 |
International physical activity questionnaire (Kcal/week) | 10432 ± 4426 | 11902 ± 6459 | 0.11 |
Medical history | |||
Hypertension | 29 (53.7) | 203 (49.6) | 0.57 |
Diabetes mellitus | 8 (14.8) | 79 (19.3) | 0.43 |
Dyslipidemia | 5 (9.3) | 47 (11.5) | 0.64 |
Coronary artery disease | 1 (1.9) | 18 (4.4) | 0.38 |
Charlson Comorbidity Index | 1.9 ± 1.5 | 1.4 ± 1.5 | 0.013 |
Functional performance | |||
Frail | 11 (20.4) | 31 (7.6) | 0.005 |
Walking speed | 1.3 ± 0.4 | 1.4 ± 0.4 | 0.063 |
Male | 1.4 ± 0.5 | 1.5 ± 0.5 | 0.23 |
Female | 1.3 ± 0.3 | 1.3 ± 0.4 | 0.99 |
Cognitive impairment | 19 (35.2) | 138 (33.7) | 0.88 |
Depressive symptoms | 1 (1.9) | 15 (3.7) | 0.71 |
Malnutrition | 12 (22.2) | 17 (4.2) | <0.001 |
Laboratory test results | |||
Fasting blood glucose (mg/dL) | 96.1 ± 27.3 | 103.2 ± 30.0 | 0.11 |
Uric acid (mg/dL) | 6.1 ± 1.5 | 5.9 ± 1.4 | 0.44 |
Serum creatinine (mg/dL) | 0.9 ± 0.3 | 0.8 ± 0.3 | 0.35 |
Alanine aminotransferase (IU/mL) | 27.1 ± 23.8 | 28.7 ± 21.9 | 0.62 |
Albumin (mg/dL) | 4.4 ± 0.2 | 4.4 ± 0.3 | 0.64 |
Free androgen index | 20.4 ± 14.9 | 17.1 ± 18.3 | 0.15 |
Homeostasis model assessment of insulin resistance | 1.5 ± 0.9 | 1.7 ± 1.1 | 0.26 |
High‐sensitivity C‐reactive protein (mg/dL) | 0.2 ± 0.4 | 0.2 ± 0.4 | 0.62 |
Homocysteine (μmol/L) | 14.8 ± 5.5 | 14.3 ± 7.0 | 0.65 |
Insulin‐like growth factor‐1 (ng/mL) | 116.2 ± 50.5 | 121.2 ± 52.5 | 0.52 |
Dehydroepiandrosterone (μg/dL) | 74.8 ± 42.8 | 94.1 ± 68.6 | <0.005 |
Vitamin D3 (ng/mL) | 25.2 ± 6.1 | 25.1 ± 8.0 | 0.87 |
Serum myostatin (pg/mL) | 4390 ± 2336 | 4978 ± 2313 | 0.080 |
Myostatin status (tertiles) | 0.043 | ||
Low | 26 (48.2) | 136 (33.3) | |
Medium | 14 (25.9) | 137 (33.4) | |
High | 14 (25.9) | 136 (33.3) | |
Activin A (pg/mL) | 521.2 ± 161.1 | 532.1 ± 177.0 | 0.66 |
Follistatin (pg/mL) | 1688 ± 525 | 1577 ± 631 | 0.22 |
Among known risk factors for sarcopenia—specifically, the inflammatory marker C‐reactive protein and hormonal profiles—only serum DHEA levels were significantly lower among subjects with low vs. normal RASM. Although there were no significant between‐group differences in serum activin or follistatin levels, the low RASM group serum tended to have lower myostatin levels, and subjects with low RASM were significantly more likely to have serum myostatin in the lowest tertile.
Table 2 summarizes the logistic regression results. In Model 4 (adjusted for age, sex, smoking status, alcohol consumption, Charlson Comorbidity Index score, total body fat percentage, malnutrition, DHEA, and myostatin status), male sex, malnutrition, DHEA, and low myostatin status were all independent risk factors for low RASM.
Table 2.
Independent predictors of low muscle mass among otherwise healthy community‐living older adults
(n = 463) | Model 1a | Model 2b | Model 3c | Model 4d | ||||
---|---|---|---|---|---|---|---|---|
Odds ratio (95% CI) | P‐value | Odds ratio (95% CI) | P‐value | Odds ratio (95% CI) | P‐value | Odds ratio (95% CI) | P‐value | |
Age (years) | 1.05 (1.01–1.08) | 0.005 | 1.04 (1.00–1.08) | 0.071 | 1.01 (0.97–1.06) | 0.597 | 1.02 (0.97–1.07) | 0.423 |
Malee | 2.14 (1.29–4.51) | 0.006 | 2.39 (1.15–4.96) | 0.02 | 3.28 (1.47–7.29) | 0.004 | 3.60 (1.30–9.92) | 0.013 |
Smoking | 0.99 (0.74–1.32) | 0.934 | 0.97 (0.71–1.32) | 0.841 | 1.00 (0.73–1.36) | 0.976 | ||
Alcohol consumption | 1.07 (0.79–1.45) | 0.672 | 1.12 (0.82–1.55) | 0.476 | 1.12 (0.81–1.55) | 0.507 | ||
Charlson Comorbidity Index | 1.12 (0.90–1.41) | 0.31 | 1.03 (0.81–1.31) | 0.837 | 1.04 (0.81–1.33) | 0.755 | ||
Frailty | 1.58 (0.64–3.89) | 0.323 | 1.57 (0.61–4.00) | 0.35 | ||||
Malnutrition | 5.16 (2.11–12.61) | <0.001 | 4.39 (1.56–12.36) | 0.005 | ||||
Dehydroepiandrosterone | 0.99 (0.99–1.00) | 0.034 | 0.99 (0.99–1.00) | 0.019 | ||||
Total body fat percentage | 0.99 (0.94–1.05) | 0.786 | ||||||
Myostatin | ||||||||
Low vs. high | 3.23 (1.49–7.01) | 0.003 | ||||||
Medium vs. high | 1.17 (0.51–2.71) | 0.713 |
Adjusted for age and sex.
Adjusted for age, sex, smoking, alcohol consumption, and Charlson Comorbidity Index.
Adjusted for age, sex, smoking, alcohol consumption, Charlson Comorbidity Index, malnutrition, and dehydroepiandrosterone.
Adjusted age, sex, smoking, alcohol consumption, Charlson Comorbidity Index, malnutrition, dehydroepiandrosterone, and myostatin tertile.
Female and male were assigned values of 0 and 1, respectively.
Due to different muscle mass between the sexes, we performed separate logistic regression analyses in men and women (Table 3); lower DHEA level and low myostatin status were significantly associated with low RASM in men, whereas only malnutrition was directly related to low RASM in women.
Table 3.
Independent predictors of low muscle mass in men and women aged ≥53 years
Men (n = 229) | Women (n = 234) | |||
---|---|---|---|---|
Odds ratio (95% CI) | P‐value | Odds ratio (95% CI) | P‐value | |
Age | 1.03 (0.98–1.09) | 0.249 | 1.02 (0.94–1.10) | 0.703 |
Smoking | 1.02 (0.72–1.45) | 0.917 | 1.34 (0.57–3.12) | 0.502 |
Alcohol consumption | 1.07 (0.74–1.56) | 0.719 | 1.58 (0.79–3.15) | 0.197 |
Charlson Comorbidity Index | 0.89 (0.64–1.23) | 0.474 | 1.18 (0.80–1.73) | 0.398 |
Frailty | 2.20 (0.69–6.98) | 0.183 | 0.37 (0.05–3.00) | 0.353 |
Malnutrition | 2.59 (0.65–10.31) | 0.178 | 13.59 (2.22–83.25) | 0.005 |
Dehydroepiandrosterone | 0.99 (0.98–1.00) | 0.009 | 1.00 (0.99–1.01) | 0.76 |
Total body fat percentage | 0.96 (0.90–1.04) | 0.31 | 1.06 (0.97–1.16) | 0.236 |
Myostatin | ||||
Low vs. High | 4.89 (1.79–13.37) | 0.002 | 1.47 (0.40–5.49) | 0.563 |
Medium vs. High | 1.55 (0.56–4.31) | 0.40 | 0.38 (0.07–2.18) | 0.277 |
In post hoc analyses, there was no significant difference in serum myostatin levels between subjects aged 53–70 vs. ≥70 years (P = 0.085) or significant associations in either sex between serum myostatin and follistatin (men: P = 0.921; women P = 0.410); however, an association between myostatin and total body fat percentage was evident in men (men: P = 0.041; women: P = 0.704).
Discussion
To the best of our knowledge, this is the first report of the association between serum myostatin and lower skeletal muscle mass among healthy community‐living older adults; lower serum DHEA levels and low serum myostatin status were independent risk factors of low RASM in men. Although the muscle‐wasting effect of myostatin is well‐established,13, 14 the relationship between serum myostatin and skeletal muscle mass in humans is complex and remains controversial; moreover, reported associations were observed in patients with COPD or heart failure.13, 15, 23, 24 Age‐related loss of muscle mass was associated inversely with serum myostatin among frail older adults,13 and circulating myostatin in male patients with COPD also negatively correlated with skeletal mass calculated using a validated formula.14 Conversely, others have reported skeletal muscle wasting associated with lower myostatin levels, especially in heart failure patients with compensatory status, cachexia, or undertaking exercise training.15, 23, 24 This inconsistent evidence makes it difficult to assess the potential of serum myostatin as a biomarker for sarcopenia.
Our finding that low serum myostatin was an independent risk factor for lower RASM in healthy older adults appears contradictory to current understanding. One explanation may relate to the myostatin splice variant protein, which binds to myostatin and antagonizes canonical signalling25; Jeanplong et al. reported that an energy‐restricted diet reduced the semitendinosus muscle mass of young ewes and that myostatin activity was inhibited by increased myostatin splice variant expression, implying an important influence of nutritional status on the action of myostatin in skeletal muscle development.25 Another reason could be differences in the age distributions of study cohorts. Yarasheski et al. observed that serum myostatin was higher among women aged 76–92 years old than younger ones,13 indicating that age might influence myostatin expression; however, we found no significant difference in serum myostatin between subjects aged 53–70 vs. ≥70 years.
Follistatin is a myostatin antagonist that maintains tissue homeostasis. Interestingly, we found no significant association between serum follistatin and myostatin in either sex, perhaps because the liver usually secretes follistatin immediately after exercise and our participants' blood samples were all taken early in the morning, before daily activities. Myostatin also inhibits or promotes adipogenesis, depending on the circumstances26; although its action is chiefly inhibitory, myostatin may also have an adipogenic effect, by promoting mesenchymal stem cell differentiation.27 In our study, we found an association between myostatin and adipose tissue in men, but not in women. The pathophysiology of myostatin in adipose tissue is very complex and incompletely understood; it is thought to be influenced by insulin resistance,28 insulin‐like growth factor‐1,29 and the sex steroid precursor DHEA,30, 31 which was associated with low muscle mass among male participants in our study. Given these complicated relationships, a longitudinal study is needed to clarify whether low serum myostatin is a cause or a consequence of low muscle mass.
The risk of becoming malnourished increases with advancing age, due to decreased appetite, poor digestion, polypharmacy, cognitive impairment, or depressed mood, as well as acute or chronic medical conditions and socio‐economic factors. Although only 6.3% of ILAS subjects were malnourished, malnutrition and lower skeletal muscle mass were strongly interrelated, consistent with other studies in older men or women.32, 33, 34, 35 Among people with heart failure, malnutrition plays a prominent role in muscle loss and sarcopenia, as well as disease severity,36 and in a prospective cohort, lower Mini Nutritional Assessment score independently predicted muscle wasting and mortality.34 Among postmenopausal women receiving weight‐loss intervention, higher protein intake prevented loss of lean body mass.33 Hence, nutritional factors should be taken into account when evaluating serum myostatin as a sarcopenia biomarker. Among ILAS subjects, female sex was not a risk factor for low RASM or the association between serum myostatin and low muscle mass. Sex is an important determinant of reduced muscle strength and age‐related diminution of muscle mass.37 Men generally start losing muscle mass when serum testosterone drops after age 40.38 Women may gradually lose 10–15% of their muscle mass between age 25 and menopause onset, rising to 2% annually thereafter.39
The prevalence of sarcopenia among community‐dwelling adults in Minnesota, USA, as determined by dual‐energy X‐ray absorptiometry, was 10% for men and 8% for women aged 60–69 years, and 40% for men and 18% for women aged over 80 years,2 and whole body magnetic resonance imaging has shown that men lose more skeletal muscle mass with advancing age than do women.40 Men and women in a longitudinal study all lost significant total and leg lean muscle mass over 3 years, with greater proportional and absolute lean mass diminution in men.41 This evidence suggests that male sex is a potential risk factor for low muscle mass, possibly through mechanisms associated with age‐related decline of endocrine factors, such as androgens, growth hormone, and insulin‐like growth factor‐1.40
Serum DHEA peaks during puberty declines to 20% of the maximal value in later life, and falls to only 5% after age 85.42, 43, 44 The waning DHEA level parallels other age‐related changes, such as muscle wasting.40 Consistent with other studies,30, 46, 47 we found serum DHEA to be significantly associated with lower RASM, with a stronger association in older men than among women. Balagopa et al. reported that myosin heavy‐chain synthesis declined progressively with age, and that serum DHEA was significantly associated with the fractional synthesis rate.45 Others found that DHEA was positively correlated with lean body mass in men aged over 60 years,30 and have reported that serum DHEA level was an independent associated factor for calf‐muscle area.47 However, data supporting an effect of DHEA supplementation in preventing sarcopenia and frailty are equivocal.48, 49, 50
Study strengths and limitations
As the first investigation on this specific question, our results have important implications for further research. Moreover, we have made comprehensive adjustments for major factors related to skeletal muscle mass (high‐sensitivity C‐reactive protein, hormone profiles, vitamin D, nutritional status, cognitive function, physical activity), which previous studies did not take into account. Nevertheless, there are several noteworthy limitations. First, due to the cross‐sectional design, the causality of relationships between the biomarkers assayed and muscle mass could not be established; low muscle mass may either cause or result from low serum myostatin. Second, the dynamic effect of myostatin‐activin‐follistatin interaction on skeletal muscle mass is uncertain. Third, low serum myostatin might result from low muscle mass among otherwise healthy older adults not currently experiencing rapid muscle loss.
Conclusions
Male sex, malnutrition, lower serum DHEA, and low serum myostatin status were significantly associated with low muscle mass among otherwise healthy community‐living older adults in Taiwan; however, the associations with low serum myostatin and low skeletal muscle mass were observed only in men, not women.
Although myostatin signalling is a potential pharmaceutical target for sarcopenia, our results do not support using serum myostatin levels to diagnose sarcopenia nor to monitor its response to treatments. Further research to clarify the potential of myostatin as a biomarker is needed.
Conflict of interest
All authors declare that they have no conflict of interest.
Acknowledgements
This study was supported by the Ministry of Science and Technology, Taiwan (MOST 104‐2633‐B‐400‐001 and MOST 105‐3011‐B‐010‐001).
The authors certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia and Muscle.51 Dr. David Neil (PhD), of ContentEd Net (Taiwan), provided editorial assistance on behalf of Taipei Veterans General Hospital.
Peng, L.‐N. , Lee, W.‐J. , Liu, L.‐K. , Lin, M.‐H. , and Chen, L.‐K. (2018) Healthy community‐living older men differ from women in associations between myostatin levels and skeletal muscle mass. Journal of Cachexia, Sarcopenia and Muscle, 9: 635–642. 10.1002/jcsm.12302.
References
- 1. Holloszy JO. The biology of aging. Mayo Clin Proc 2000;75:S3–S8, discussion S8–S9. [PubMed] [Google Scholar]
- 2. Melton LJ 3rd, Kholsa S, Crowson CS, O'Connor MK, O'Fallon WM, Riggs BL. Epidemiology of sarcopenia. J Am Geriatr Soc 2000;48:625–630. [PubMed] [Google Scholar]
- 3. Wolfson L, Judge J, Whipple R, King M. Strength is a major factor in balance, gait, and the occurrence of falls. J Gerontol A Biol Sci Med Sci 1995;50: Spec No.:64–67. [DOI] [PubMed] [Google Scholar]
- 4. Visser M, Kritchevsky SB, Goodpaster BH, Newman AB, Nevitt M, Stamm E, et al. Leg muscle mass and composition in relation to lower extremity performance in men and women aged 70 to 79: the health, aging and body composition study. J Am Geriatr Soc 2002;50:897–904. [DOI] [PubMed] [Google Scholar]
- 5. Tyrovolas S, Koyanagi A, Olaya B, Ayuso‐Mateos JL, Miret M, Chatterji S, et al. The role of muscle mass and body fat on disability among older adults: a cross‐national analysis. Exp Gerontol 2015;69:27–35. [DOI] [PubMed] [Google Scholar]
- 6. Srikanthan P, Karlamangla AS. Muscle mass index as a predictor of longevity in older adults. Am J Med 2014;127:547–553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Argiles JM, Busquets S, Felipe A, López‐Soriano FJ. Molecular mechanisms involved in muscle wasting in cancer and ageing: cachexia versus sarcopenia. Int J Biochem Cell Biol 2005;37:1084–1104. [DOI] [PubMed] [Google Scholar]
- 8. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF‐beta superfamily member. Nature 1997;387:83–90. [DOI] [PubMed] [Google Scholar]
- 9. McNally EM. Powerful genes–myostatin regulation of human muscle mass. N Engl J Med 2004;350:2642–2644. [DOI] [PubMed] [Google Scholar]
- 10. Zimmers TA, Davies MV, Koniaris LG, Haynes P, Esquela AF, Tomkinson KN, et al. Induction of cachexia in mice by systemically administered myostatin. Science 2002;296:1486–1488. [DOI] [PubMed] [Google Scholar]
- 11. Hosoyama T, Yamanouchi K, Nishihara M. Role of serum myostatin during the lactation period. J Reprod Dev 2006;52:469–478. [DOI] [PubMed] [Google Scholar]
- 12. Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004;350:2682–2688. [DOI] [PubMed] [Google Scholar]
- 13. Yarasheski KE, Bhasin S, Sinha‐Hikim I, Pak‐Loduca J, Gonzalez‐Cadavid NF. Serum myostatin‐immunoreactive protein is increased in 60‐92 year old women and men with muscle wasting. J Nutr Health Aging 2002;6:343–348. [PubMed] [Google Scholar]
- 14. Ju CR, Chen RC. Serum myostatin levels and skeletal muscle wasting in chronic obstructive pulmonary disease. Respir Med 2012;106:102–108. [DOI] [PubMed] [Google Scholar]
- 15. Furihata T, Kinugawa S, Fukushima A, Takada S, Homma T, Masaki Y, et al. Serum myostatin levels are independently associated with skeletal muscle wasting in patients with heart failure. Int J Cardiol 2016;220:483–487. [DOI] [PubMed] [Google Scholar]
- 16. Guigoz Y. The Mini Nutritional Assessment (MNA) review of the literature–What does it tell us? J Nutr Health Aging 2006;10:466–485, discussion 485–487. [PubMed] [Google Scholar]
- 17. Folstein MF, Folstein SE, McHugh PR. “Mini‐mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. [DOI] [PubMed] [Google Scholar]
- 18. Hoyl MT, Alessi CA, Harker JO, Josephson KR, Pietruszka FM, Koelfgen M, et al. Development and testing of a five‐item version of the geriatric depression scale. J Am Geriatr Soc 1999;47:873–878. [DOI] [PubMed] [Google Scholar]
- 19. Qu NN, Li KJ. Study on the reliability and validity of international physical activity questionnaire (Chinese Vision, IPAQ). Zhonghua Liu Xing Bing Xue Za Zhi 2004;25:265–268. [PubMed] [Google Scholar]
- 20. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383. [DOI] [PubMed] [Google Scholar]
- 21. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146–M156. [DOI] [PubMed] [Google Scholar]
- 22. Chen LK, Liu LK, Woo J, Assantachai P, Auyeung TW, Bahyah KS, et al. Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc 2014;15:95–101. [DOI] [PubMed] [Google Scholar]
- 23. Christensen HM, Kistorp C, Schou M, Keller N, Zerahn B, Frystyk J, et al. Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status. Endocrine 2013;43:626–634. [DOI] [PubMed] [Google Scholar]
- 24. Lenk K, Erbs S, Höllriegel R, Beck E, Linke A, Gielen S, et al. Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure. Eur J Prev Cardiol 2012;19:404–411. [DOI] [PubMed] [Google Scholar]
- 25. Jeanplong F, Osepchook CC, Falconer SJ, Smith HK, Bass JJ, McMahon CD, et al. Undernutrition regulates the expression of a novel splice variant of myostatin and insulin‐like growth factor 1 in ovine skeletal muscle. Domest Anim Endocrinol 2015;52:17–24. [DOI] [PubMed] [Google Scholar]
- 26. Deng B, Zhang F, Wen J, Ye S, Wang L, Yang Y, et al. The function of myostatin in the regulation of fat mass in mammals. Nutr Metab (Lond) 2017;14:29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Artaza JN, Bhasin S, Magee TR, Reisz‐Porszasz S, Shen R, Groome NP, et al. Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells. Endocrinology 2005;146:3547–3557. [DOI] [PubMed] [Google Scholar]
- 28. Dong J, Dong Y, Dong Y, Chen F, Mitch WE, Zhang L. Inhibition of myostatin in mice improves insulin sensitivity via irisin‐mediated cross talk between muscle and adipose tissues. Int J Obes (Lond) 2016;40:434–442. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Huh JY, Dincer F, Mesfum E, Mantzoros CS. Irisin stimulates muscle growth‐related genes and regulates adipocyte differentiation and metabolism in humans. Int J Obes(Lond) 2014;38:1538–1544. [DOI] [PubMed] [Google Scholar]
- 30. Abbasi A, Duthie EH Jr, Sheldahl L, Wilson C, Sasse E, Rudman I, et al. Association of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community‐dwelling older men and women. J Am Geriatr Soc 1998;46:263–273. [DOI] [PubMed] [Google Scholar]
- 31. McNelis JC, Manolopoulos KN, Gathercole LL, Bujalska IJ, Stewart PM, Tomlinson JW, et al. Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake. Am J Physiol Endocrinol Metab 2013;305:E1134–E1144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Bahat G, Saka B, Tufan F, Akin S, Sivrikaya S, Yucel N, et al. Prevalence of sarcopenia and its association with functional and nutritional status among male residents in a nursing home in Turkey. Aging Male 2010;13:211–214. [DOI] [PubMed] [Google Scholar]
- 33. Bopp MJ, Houston DK, Lenchik L, Easter L, Kritchevsky SB, Nicklas BJ. Lean mass loss is associated with low protein intake during dietary‐induced weight loss in postmenopausal women. J Am Diet Assoc 2008;108:1216–1220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Saitoh M, Dos Santos MR, Ebner N, Emami A, Konishi M, Ishida J, et al. Nutritional status and its effects on muscle wasting in patients with chronic heart failure: insights from studies investigating co‐morbidities aggravating heart failure. Wien Klin Wochenschr 2016;128:497–504. [DOI] [PubMed] [Google Scholar]
- 35. Velázquez Alva Mdel C, Irigoyen Camacho ME, Delgadillo Velázquez J, Lazarevich I. The relationship between sarcopenia,undernutrition, physical mobility and basic activities of daily living in a group of elderly women of Mexico City. Nutr Hosp 2013;28:514–521. [DOI] [PubMed] [Google Scholar]
- 36. Saitoh M, Rodrigues Dos Santos M, von Haehling S. Muscle wasting in heart failure. The role of nutrition. Wien Klin Wochenschr 2016;128:455–465. [DOI] [PubMed] [Google Scholar]
- 37. Gallagher D, Heymsfield SB. Muscle distribution: variations with body weight, gender, and age. Appl Radiat Isot 1998;49:733–734. [DOI] [PubMed] [Google Scholar]
- 38. Vermeulen A, Goemaere S, Kaufman JM. Testosterone, body composition and aging. J Endocrinol Invest 1999;22:110–116. [PubMed] [Google Scholar]
- 39. Frontera WR, Hughes VA, Fielding RA, Fiatarone MA, Evans WJ, Roubenoff R. Aging of skeletal muscle: a 12‐yr longitudinal study. J Appl Physiol (1985) 2000;88:1321–1326. [DOI] [PubMed] [Google Scholar]
- 40. Janssen I, Heymsfield SB, Wang ZM, Rl R. Skeletal muscle mass and distribution in 468 men and women aged 18–88 yr. J Appl Physiol (1985) 2000;89:81–88. [DOI] [PubMed] [Google Scholar]
- 41. Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci 2006;61:1059–1064. [DOI] [PubMed] [Google Scholar]
- 42. Bélanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez JL, et al. Changes in serum concentrations of conjugated and unconjugated steroids in 40‐ to 80‐year‐old men. J Clin Endocrinol Metab 1994;79:1086–1090. [DOI] [PubMed] [Google Scholar]
- 43. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551–555. [DOI] [PubMed] [Google Scholar]
- 44. Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H. Long‐term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 1992;75:1002–1004. [DOI] [PubMed] [Google Scholar]
- 45. Balagopal P, Rooyackers OE, Adey DB, Ades PA, Nair KS. Effects of aging on in vivo synthesis of skeletal muscle myosin heavy‐chain and sarcoplasmic protein in humans. Am J Physiol 1997;273:E790–E800. [DOI] [PubMed] [Google Scholar]
- 46. Villareal DT, Holloszy JO. DHEA enhances effects of weight training on muscle mass and strength in elderly women and men. Am J Physiol Endocrinol Metab 2006;291:E1003–E1008. [DOI] [PubMed] [Google Scholar]
- 47. Valenti G, Denti L, Maggio M, Ceda G, Volpato S, Bandinelli S, et al. Effect of DHEAS on skeletal muscle over the life span: the InCHIANTI study. J Gerontol A Biol Sci Med Sci 2004;59:466–472. [DOI] [PubMed] [Google Scholar]
- 48. Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006;355:1647–1659. [DOI] [PubMed] [Google Scholar]
- 49. Villareal DT, Holloszy JO, Kohrt WM. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf) 2000;53:561–568. [DOI] [PubMed] [Google Scholar]
- 50. Corona G, Rastrelli G, Giagulli VA, Sila A, Sforza A, Forti G, et al. Dehydroepiandrosterone supplementation in elderly men: a meta‐analysis study of placebo‐controlled trials. J Clin Endocrinol Metab 2013;98:3615–3626. [DOI] [PubMed] [Google Scholar]
- 51. von Haehling S, Morley JE, Coats AJS, Anker SD. Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2017. J Cachexia Sarcopenia Muscle 2017;8:1081–1083. [DOI] [PMC free article] [PubMed] [Google Scholar]