JCM, Vol. 11, Pages 7175: Adiponectin Is a Contributing Factor of Low Appendicular Lean Mass in Older Community-Dwelling Women: A Cross-Sectional Study

1. IntroductionAccording to the International Classification of Diseases (ICD-10-MC), sarcopenia is a gradual and generalized muscle disease that consists of the progressive loss of muscle mass, muscle strength, and/or physical function [1]. Older people with loss of muscle mass experience a marked decline in strength, and physical function [2]. Low muscle mass and function may result in a reduced quality of life, a loss of independence, a need for long-term care, an increased risk of falls and fractures, and mortality [1,2]. Cognitive impairment, fear of falling, depressive symptoms, a poor or fair self-perception of health, and inflammation are a few of the characteristics that might predispose a person to sarcopenia [3].A continuous, sterile, low-grade inflammation known as “inflammaging” may contribute to the clinical symptoms of chronic diseases [4,5,6]. Thus, inflammaging can contribute to the etiology of sarcopenia and to the dysfunction of skeletal muscle tissue, establishing a vicious cycle of inflammation and muscle wasting [5]. High levels of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNF), interferon (IFN), granulocyte stimulating factor, high-temperature monocytes, and serine protease are frequently associated with deteriorated physical function, reduced muscle mass, and decreased muscular strength in older individuals [7].Moreover, previous research has demonstrated a negative correlation between inflammatory biomarkers and chronic conditions [6]. In older people with sarcopenia, high levels of IL-6 and soluble tumor necrosis factor receptor 2 (sTNFr2) were reported [4]. Additionally, sarcopenia can affect the signaling pathway for adiponectin activation [8] to prevent muscle atrophy and inflammation while fostering muscle regeneration [8,9,10]. Despite the current literature indicating a link between biomarkers and sarcopenia, especially in women [8], few studies have used DXA to assess appendicular lean mass (ALM). With this regard, current literature often estimates lean mass indirectly or infers muscle mass using a muscular performance test. Since muscle and adipose tissue are related to the release of adipocytokines, it is imperative to assess them using the most recommended method [7,8,9,10]. Furthermore, few studies provide information on the association between muscle mass and a large panel of biomarkers analyzed simultaneously.It is challenging to identify a single biomarker that can characterize sarcopenia due to the complex pathophysiology and the multiple pathways that cause muscle wasting and sarcopenia [4,8]. Therefore, the aims of the present study were: (1) To classify older community-dwelling women according to the ALM using dual-energy X-ray absorptiometry (DXA), one of the most recommended methods to assess the body composition, as with normal or low ALM. (2) To compare anthropometric parameters, muscle strength, and a broad panel of biomarkers (IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF, sTNFr1, sTNFr2, adiponectin, leptin, resistin, and BDNF) between older community-dwelling women groups stratified according to the ALM. (3) To investigate contributing factors to low ALM in older community-dwelling women. (4) To contribute to the development of strategies for early diagnosis and/or treatment of low muscle mass in sarcopenia and other conditions affected by muscle mass in older women. 4. DiscussionTo our knowledge, this is the first study to assess the association between appendicular muscle mass using DXA and a broad panel of blood biomarkers related to sarcopenia. In our screening, low appendicular muscle mass or the risk of sarcopenia was present in 69% of the community-dwelling older women. Handgrip strength (HGS), total fat mass, and trunk fat mass were significantly lower in the low ALM group. Regarding biomarkers, plasma levels of adiponectin, sTNFr1, and IL-8 were higher in the low ALM group and demonstrated an association with adiponectin, sTNFr1, and IL-8 with ALM. In clinical terms, community-dwelling older women with less muscle mass had higher blood levels of these biomarkers (Table 2). Of note, our post-hoc analysis from linear multiple regression (correlation coefficient of 0.26 between ALM and adiponectin) revealed a large effect size of 0.35 and a power of 0.85 [14].Noteworthy, older women with low ALM also presented low HGS, as in cases of confirmed sarcopenia [1,2,14,15]. There is still debate concerning the relationship between biomarkers and sarcopenia [4,5,7,8,10,16,17]. This is because once a skeletal muscle has become a secretory organ, inflammatory and muscle cells can work together to produce the myokines that induce sarcopenia [5,18,19].There is growing evidence suggesting that chronic low-grade inflammation, or inflammation, could play a key role in the development of sarcopenia [4,5,7,10,15,16,17,18]. Thus, high blood level of proinflammatory biomarkers, including IL-6, IL-8, and IL-15, can affect skeletal muscle mass and are suggestive of inflammation, whereas high blood level of anti-inflammatory biomarkers, i.e., IL-4, IL-10, and IL-15 can counteract the generation and activity of proinflammatory cytokines and consequently the muscle atrophy and sarcopenia [5,10,17,18,19,20,21,22].Among all evaluated biomarkers, adiponectin, IL-8, and sTNFr1 correlated negatively with ALM (Table 3). It is unclear whether IL-8, a chemotactic factor that leads to inflammation, contributes to sarcopenia [10,23]. As seen in cachexia and frailty, higher levels of IL-8 indicate a more prepared and active innate immune response [24]. The findings of the present study reinforce a previous work, including older people from the United Kingdom, which demonstrated the effect between higher levels of IL-8, and lower ALM, i.e., subjects with higher risk of sarcopenia [25].Thus, the findings of the study are consistent with studies that found an increase in sTNFr1 blood levels to be negatively linked to muscle mass parameters [26]. Furthermore, over a five-year period, computed tomography as well as the Jamar dynamometer revealed a significant link between increased sTNFr1 blood levels and loss of muscle mass and strength [26]. However, Lustosa et al. (2017) found greater sTNFr1 blood levels in older individuals who were not sarcopenic [27]. In this sense, as the connection between sTNFr1 and sarcopenia or low muscle mass remains unclear, further research is needed.Sarcopenia is linked to the adipokines, i.e., leptin and adiponectin [16], which are secreted by adipose and musculoskeletal tissues [10]. Currently, it is unclear whether leptin and muscle mass or sarcopenia interact [5,10,28]. As far as we know, leptin blood levels have proinflammatory effects [29]. The study by Li et al. (2019), which included older sarcopenic and nonsarcopenic individuals, showed that sarcopenic individuals had considerably higher leptin blood levels, which were linked to the severity and risk of sarcopenia [30]. In accordance, Kohara et al. (2011) observed that high leptin blood levels are greater in individuals with sarcopenia and visceral obesity than in individuals with only one condition, suggesting that leptin blood levels are associated with sarcopenia, independent of visceral fat [31]. Although leptin blood levels were lower in the low ALM group in our sample, this difference was not statistically significant.A biomarker with antidiabetic, anti-inflammatory, and antiatherogenic properties is adiponectin [8,16,32]. It is produced by skeletal muscle and adipose tissue, has metabolic effects primarily in the liver and skeletal muscle, and modulates inflammatory processes by preventing the production of proinflammatory markers, including IL-6, IL-18, and TNF- [16,32,33]. A positive muscle function regulator also directly produces injured fibers and triggers the metabolism of muscle cells [8,9,31,32,33].According to a meta-analysis, including seven studies, those with sarcopenia (n = 557) were more likely to have higher levels of adiponectin [8]. In addition, the prevalence of sarcopenia was reported to differ between men and women, and meta-regression analysis revealed an important role for females in explaining the association between sarcopenia and adiponectin, suggesting that women have higher levels of adiponectin than men, as they seem to express more plasma adiponectin than men, regardless of fat mass and BMI, due to the influence of sex hormones [8]. However, adiponectin blood levels in studies using DXA did not differ significantly between subgroups in analysis [8]. In another line, our findings are consistent with the results of Rossi et al. (2019), who compared the inflammatory profile of the Brazilian seniors and observed that the sarcopenic group had a higher concentration of adiponectin [16]. Although increased adiponectin levels in sarcopenia are still being studied [4,5,8,10,16], some possible mechanisms have been proposed to explain the peculiarity: down-regulation of adiponectin receptor signaling [8,32], deposition of adipose tissue in muscles that may influence adiponectin expression [8,34], and activation of catabolism related to the presence of other comorbidities [8,33]. Of note, adiponectin blood level was significantly higher in the low ALM group in our sample and was inversely associated with ALM (r = −0.259; p = 0.02) explaining 14% of the ALM variability (β = −0.39; R2 = −0.14; pTherapeutic targets for the treatment of sarcopenia might include anti-inflammatory cytokines [5,33]. It is generally agreed upon that regulating IL-6 levels may be a therapeutic approach to keep skeletal muscle healthy [5,33,35]. Considering the evidence of adiponectin’s anti-inflammatory and regenerative role, our findings point to it as a potential biomarker linked to muscle damage brought on by low ALM and encourage more study into diagnostics and therapy.The development of chronic inflammation and sarcopenia may be influenced by adipose tissue, which can also lead to sarcopenia and sarcopenic obesity [10,16,35]. As a result, obese people who have more visceral subcutaneous adipose tissue are more likely to have greater levels of adiponectin, indicating that the distribution of adipose tissue also influences the release of adipokines [10,34]. Thus, understanding that body fat, especially trunk fat, is metabolically active and secretes inflammatory biomarkers, including adiponectin [34], it is important to highlight that the best model that explained the low appendicular muscle mass was adiponectin and the trunk fat mass (Table 3) in older community-dwelling women. In addition, to clarify the relationship between ALM, fat mass, and adiponectin, we evaluated additional models using adiponectin as a dependent variable, including total fat mass, total lean mass, and ALM as independent variables. Therefore, we found that ALM was the only significant predictor [F (1, 69) = 12.79; p2 = 0.14; β = −0.39], explaining 14% of adiponectin, reinforcing the association between muscle mass and adiponectin independently of body fat.

When the model of the analysis was adjusted for age, the results remained the same (R = 0.80; adjusted R2 = 0.63; p < 0.001), suggesting that trunk fat mass and adiponectin are possible predictors of appendicular muscle mass in older community-dwelling women. Thus, our findings together allow us to speculate on the involvement of adiponectin in the modulation of inflammatory control and ALM, influencing positively the balance between the anti-inflammatory (IFN, IL-4, IL-5, and IL-10) and proinflammatory biomarkers (IL-2, IL-6, sTNFr2, and TNF) in community-dwelling older women. However, the biomarkers were dosed systemically in our group, but possibly future research that measures the biomarkers directly in the muscle would provide more illuminating results. More research advances are needed to explore whether there is a cause-effect relationship in the interaction between muscle and biomarkers.

Notably, there was no difference in the clinical, sociodemographic, cultural, or functional variables between the older, normal, and low ALM groups, showing there was no data interpretation bias. The present study’s stronger points were its methodological rigor, use of one of the most recommended methods to measure body composition, participants fasting prior to body composition and blood level assessments, the blinding of the evaluators to the DXA and strength test, as well as the rigor in the exclusion criteria used.

The contribution of the present study is to show that high levels of adiponectin are associated with lower appendicular muscle mass in community-dwelling elderly women. The practical implications of this study are as follows: (1) Older women with lower ALM assessed by DXA also have lower HGS. Low levels of these clinical features are directly associated with sarcopenia in older women; (2) higher adiponectin levels were associated with lower appendicular muscle mass among community-dwelling older women; (3) contribution to clinical or public health strategies aimed at early assessment and diagnosis of sarcopenia and other diseases related to low muscle mass in old women. The limitation of this study was the short observation time (cross-sectional study); only older community-dwelling women were investigated; our findings should not be extrapolated to the population of clinical settings, long-term care facilities, or hospital environments; and we did not assess a cutoff point for adiponectin to predict ALM. Future studies that determine a cutoff point for adiponectin based on ALM in both sexes may further enhance our understanding of the association of these variables with sarcopenia.

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