Mylène Aubertin-Leheudre

Biomarkers of sarcopenia in clinical trials—recommendations from the International Working Group on Sarcopenia

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.

Menopause and sarcopenia : A potential role for sex hormones.

Menopause is associated with a decline in estrogen levels, which could lead to an increase in visceral adiposity as well as a decrease in bone density, muscle mass and muscle strength. This decline in muscle mass, known as sarcopenia, is frequently observed in postmenopausal women. Potential causes of sarcopenia include age-related changes in the hormonal status, low levels of physical activity, reduced protein intake and increased oxidative stress. However, the role of sex hormones, specifically estrogens, on the onset of sarcopenia is controversial. Preventing sarcopenia and preserving muscle strength are highly relevant in order to prevent functional impairment and physical disability. To date, resistance training has been shown to be effective in attenuating age-related muscle loss and strength. However, results on the effect of hormonal supplementation to treat or prevent sarcopenia are contradictory. Further research is needed to identify other potential mechanisms of sarcopenia as well as effective interventions for the prevention and treatment of sarcopenia. Therefore, the purpose of this review will be to examine the role of sex hormonal status in the development of sarcopenia. We will also overview the physical as well as metabolic consequences of sarcopenia and the efficiency of different interventions for the prevention and treatment of sarcopenia.

Effect of sarcopenia on cardiovascular disease risk factors in obese postmenopausal women.

Objective: To compare sarcopenic‐obese and obese postmenopausal women for risk factors predisposing to cardiovascular disease (CVD) and determine whether there may be a relationship between muscle mass and metabolic risk in obese postmenopausal women.

Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans

Mitochondrial dysfunction is implicated in skeletal muscle atrophy and dysfunction with aging, with strong support for an increased mitochondrial‐mediated apoptosis in sedentary rodent models. Whether this applies to aged human muscle is unknown, nor is it clear whether these changes are caused by sedentary behavior. Thus, we examined mitochondrial function [respiration, reactive oxygen species (ROS) emission, and calcium retention capacity (CRC)] in permeabilized myofibers obtained from vastus lateralis muscle biopsies of healthy physically active young (23.7±2.7 yr; mean±sd) and older (71.2±4.9 yr) men. Although mitochondrial ROS and maximal respiratory capacity were unaffected, the acceptor control ratio was reduced by 18% with aging, suggesting mild uncoupling of oxidative phosphorylation. CRC was reduced by 50% with aging, indicating sensitization of the mitochondrial permeability transition pore (mPTP) to apoptosis. Consistent with the mPTP sensitization, older muscles showed a 3‐fold greater fraction of endonuclease G (a mitochondrial proapoptotic factor)‐positive myonuclei. Aged muscles also had lower mitophagic potential, based on a 43% reduction in Parkin to the voltage‐dependent anion channel (VDAC) protein ratio. Collectively, these results show that mitochondrial‐mediated apoptotic signaling is increased in older human muscle and suggest that accumulation of dysfunctional mitochondria with exaggerated apoptotic sensitivity is due to impaired mitophagy.—Gouspillou, G., Sgarioto, N., Kapchinsky, S., Purves‐Smith, F., Norris, B., Pion, C. H., Barbat‐Artigas, S., Lemieux, R, Taivassalo, T., Morais, J. A., Aubertin‐Leheudre, M., Hepple, R. T. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 28, 28–1621 (1633). www.fasebj.org

How to assess functional status: A new muscle quality index

Aging is associated with decreases in muscle mass, muscle strength and muscle power, with muscle strength declining at a higher rate than muscle mass, but at a lower rate than muscle power. This progressive mismatch suggests a deterioration of muscle “quality” that may lead to functional incapacities. Although it may be difficult to synthesize the concept of muscle quality, the aim of the present paper was to propose a clinical definition of muscle quality in regard to the functional status. Accordingly, the muscle strength or muscle power per unit of muscle mass ratios appear to be clinically relevant markers of muscle quality. Several mechanisms susceptible to influence these ratios have been described, among which age, gender, sex hormones, obesity, physical activity and fibrosis. Various methods to assess muscle quality in both the clinical and research fields have also been listed, with a particular interest for the tests used to measure muscle power. Finally, we proposed a clinical screening tool to detect individuals at risk of functional incapacities. Briefly, the muscle quality score is based on handgrip strength assessment by hand dynamometer, muscle mass measurement by bioelectrical analysis, and leg muscle power estimation using a chair stand test.

Plasma Alkylresorcinols and Urinary Alkylresorcinol Metabolites as Biomarkers of Cereal Fiber Intake in Finnish Women

Alkylresorcinols (AR) could be good biomarkers of consumption of fiber-rich cereal products. The aim of this study was to examine the relationship between plasma ARs or urinary AR metabolites and cereal fiber intake in women consuming their habitual diet. Twenty-five postmenopausal and 31 premenopausal women were recruited. The subjects included also vegetarians (n = 20) to obtain a broad range of cereal intake. Dietary intake, plasma ARs, and urinary AR metabolites [3,5-dihydroxybenzoic acid and 3-(3,5-dihydroxyphenyl)-1-propanoic acid] were measured. Pearsons and Partial correlation tests were done between dietary fiber intake and plasma ARs or urinary AR metabolites. Cereal fiber intake correlated significantly with plasma AR C17:0 (r = 0.387), AR C19:0 (r = 0.350), AR C21:0 (r = 0.428), AR C23:0 (r = 0.409), AR C25:0 (r = 0.283), and total AR (r = 0.406) and with urinary AR metabolites DHBA (r = 0.359) and DHPPA (r = 0.402) even after adjustment for body mass index and age, which could be confounding variables. This is the first study to show a significant correlation between plasma ARs or urinary AR metabolites and cereal fiber intake during consumption of a habitual diet. These results indicate that assay of plasma ARs or urinary AR metabolites may be used as biomarkers in epidemiologic studies in free-living populations to evaluate the role of cereal fiber intake in various diseases. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2244–8)

Effect of 6 months of exercise and isoflavone supplementation on clinical cardiovascular risk factors in obese postmenopausal women: a randomized, double-blind study.

Objective:To investigate whether 6 months of exercise combined with isoflavone supplementation could improve clinical risk factors that predispose to cardiovascular disease in obese postmenopausal women. Design:This was a randomized, double-blind, controlled trial in which 50 healthy obese postmenopausal women were divided into two groups and assigned to isoflavone supplementation (n = 25) or a placebo (n = 25) for 1 year. For the last 6 months, both groups participated in an exercise program (three times per week), at the end of which cardiovascular disease risk factors were compared between groups. Body composition (using dual-energy x-ray absorptiometry), metabolic profile (blood lipids, fasting insulin, fasting glucose, sex hormone-binding globulin, C-reactive protein) were determined at baseline and at 6 and 12 months. Results:We observed a significant effect of exercise and isoflavone supplementation on body weight, total and abdominal fat mass (kilograms and percentage), body mass index, appendicular fat-free mass, fat-free mass/fat mass ratio, and sex hormone-binding globulin, but not with exercise alone. No difference was observed for other biochemical characteristics, although the quantitative insulin sensitivity check index increased equally in both groups. Conversely, although not significant, we observed a tendency for a treatment effect on body mass index (P = 0.07) and on absolute (kilograms) (P = 0.07) and percentage of (P = 0.053) abdominal fat mass, whereas no effect of treatment was found for other variables using the Mann-Whitney test. Conclusions:Compared to an aerobic exercise program alone, 70 mg/day of isoflavones combined with exercise may promote significant improvements in body composition parameters that are known to influence cardiovascular disease risk in postmenopausal women.

Fat/fiber intakes and sex hormones in healthy premenopausal women in USA

The mechanisms by which diet affects breast cancer (BC) risk are poorly understood but a positive relationship between fat and a negative association with fiber intake and BC risk have been demonstrated. Here we study the association between dietary fat/fiber ratio and estrogen metabolism. Fifty women were recruited, 22 were included in the low fat/high fiber and 22 were in the high fat/low fiber group and 6 did not meet our criteria. Estrogens (determined in plasma, urine and feces) and dietary records were collected during 3 following days. All data were collected in winter and in summer. The high fat/low fiber group had significantly higher urinary total estrogens, estriol-3-glucuronide, 2-hydroxyestradiol, 16alpha-hydroxyestrone, and a higher 2-hydroxyestrone/4-hydroxyestrone ratio. Total fat intake correlated significantly with plasma estrone, estradiol, urinary 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestrone/4-hydroxyestrone ratio, and total urinary estrogens, even after adjustment for total fiber intake. The high fat/low fiber diet was associated with high values both for catechol and 16alpha-hydroxylated estrogens and a high 2-hydroxyestrone/4-hydroxyestrone ratio, but 2-hydroxyestrone/16alpha-hydroxyestrone ratio was not different between the groups. Our results suggest that fat affects estrogen metabolism more than does fiber and that one mechanism resulting in high estrogen values is an increased reabsorption of biliary estrogens.

Plasma alkylresorcinol metabolites as potential biomarkers of whole-grain wheat and rye cereal fibre intakes in women.

It has been demonstrated that intact plasma alkylresorcinols (AR) and urinary AR metabolites could be used as biomarkers of whole-grain intake. Thereafter, we developed the method for the plasma AR metabolites, which is more convenient and requires less sample pretreatment than the analysis of intact plasma AR. The aim of the present study is to evaluate whether AR metabolites measured in plasma, in the same population, could also be considered as useful biomarkers of cereal fibre. Fifty-six women were recruited in a cross-sectional and observational study. Dietary intake (5-d record) and plasma AR metabolites (3,5-dihydroxybenzoic acid, DHBA; 3-(3,5-dihydroxyphenyl)-1-propanoic acid, DHPPA) were measured. The relationship between plasma AR metabolites and cereal fibre intake was examined using partial correlation and stepwise regression. Cereal fibre intake correlated significantly with plasma DHBA (r 0.411; P = 0.002) and DHPPA (r 0.463; P = 0.000) even after adjustment for BMI and age. Thus, plasma AR metabolites correlate with cereal fibre intake as noted with plasma intact AR and urinary AR metabolites. We observed that plasma DHPPA was the independent predictor of cereal fibre intake, explaining 18 % of the variance (adjusted r(2) 0.176; P = 0.002). In epidemiological screening, it might be easier to obtain and to collect plasma than urine samples. In addition, the plasma AR metabolites half-life seems longer than those of intact plasma AR, and their measurements are more convenient, and faster. Thus, sum of plasma AR metabolites and more specifically plasma DHPPA seems to be good and specific biomarkers of cereal fibre intake.

Six months of isoflavone supplement increases fat-free mass in obese-sarcopenic postmenopausal women: a randomized double-blind controlled trial.

Objective:The aim of this study was to verify if six months of isoflavone supplementation could increase fat-free mass (FFM) and muscle mass index (MMI=appendicular FFM/height2) in obese–sarcopenic postmenopausal women.Design:Double-blind randomized study.Subject:Eighteen sarcopenic–obese women completed the study (12 on isoflavones and six on placebo). Body composition was measured by dual-energy X-ray absorptiometry. Subjects ingested 70 mg of isoflavones per day (44 mg of diadzein, 16 mg glycitein and 10 mg genestein) or a placebo for 24 weeks.Results:The isoflavone group increased significantly appendicular (P=0.034), leg (P=0.016) FFM and MMI (P=0.037), but not the placebo group.Conclusion:Six months of isoflavone supplementation increased FFM and MMI in obese–sarcopenic postmenopausal women.