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Determinants of bone mass in older adults with normal- and overweight derived from the crosstalk with muscle and adipose tissue.

ABSTRACT: Lower bone mass in older adults may be mediated by the endocrine crosstalk between muscle, adipose tissue and bone. In 150 community-dwelling adults (59-86 years, BMI 17-37 kg/m²; 58.7% female), skeletal muscle mass index, adipose tissue and fat mass index (FMI) were determined. Levels of myokines, adipokines, osteokines, inflammation markers and insulin were measured as potential determinants of bone mineral content (BMC) and density (BMD). FMI was negatively associated with BMC and BMD after adjustment for mechanical loading effects of body weight (r-values between -0.37 and -0.71, all p < 0.05). Higher FMI was associated with higher leptin levels in both sexes, with higher hsCRP in women and with lower adiponectin levels in men. In addition to weight and FMI, sclerostin, osteocalcin, leptin × sex and adiponectin were independent predictors of BMC in a stepwise multiple regression analysis. Muscle mass, but not myokines, showed positive correlations with bone parameters that were weakened after adjusting for body weight (r-values between 0.27 and 0.58, all p < 0.01). Whereas the anabolic effect of muscle mass on bone in older adults may be partly explained by mechanical loading, the adverse effect of obesity on bone is possibly mediated by low-grade inflammation, higher leptin and lower adiponectin levels.

SUBMITTER: Walowski CO

PROVIDER: S-EPMC10050471 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Determinants of bone mass in older adults with normal- and overweight derived from the crosstalk with muscle and adipose tissue.

Walowski Carina O CO Herpich Catrin C Enderle Janna J Braun Wiebke W Both Marcus M Hasler Mario M Müller Manfred J MJ Norman Kristina K Bosy-Westphal Anja A

Scientific reports 20230328 1

Lower bone mass in older adults may be mediated by the endocrine crosstalk between muscle, adipose tissue and bone. In 150 community-dwelling adults (59-86 years, BMI 17-37 kg/m<sup>2</sup>; 58.7% female), skeletal muscle mass index, adipose tissue and fat mass index (FMI) were determined. Levels of myokines, adipokines, osteokines, inflammation markers and insulin were measured as potential determinants of bone mineral content (BMC) and density (BMD). FMI was negatively associated with BMC and ...[more]

PMID: 36977715

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Project description:Simple Summary Irisin is a known myokine secreted mainly by the muscle that is produced after physical activity. It induces browning in the adipose tissue with a consequent increase in mitochondrial oxidation of lipids and reduction of insulin resistance; thus, it has been hypothesized that irisin was the molecule mediating most of the beneficial effects related to exercise on adipose tissue and consequently on the whole organism. In our study we observed that extreme physical inactivity induces the loss of muscle mass and function, and an increase in the body adipose tissue as expected. However, of note, circulating irisin levels were increased secondary to enhanced irisin synthesis mainly from adipose tissue rather than muscle. In addition, subjects who produced more irisin had reduced muscle impairment. Therefore, our hypothesis is that there is negative feedback within the muscle-adipose tissue crosstalk, specifically not only does the muscle influence the adipose tissue through irisin during exercise, but also the adipose tissue protects the muscle during inactivity. Abstract The detrimental effect of physical inactivity on muscle characteristics are well known. Irisin, an exercise-induced myokine cleaved from membrane protein fibronectin type III domain-containing protein-5 (FNDC5), mediates at least partially the metabolic benefits of exercise. This study aimed to assess the interplay between prolonged inactivity, circulating irisin, muscle performance, muscle fibers characteristics, as well as the FNDC5 gene expression (FNDC5ge) in muscle and adipose tissue among healthy subjects. Twenty-three healthy volunteers were tested before and after 14 days of Bed Rest, (BR). Post-BR circulating levels of irisin significantly increased, whereas body composition, muscle performance, and muscle fiber characteristics deteriorated. Among the subjects achieving the highest post-BR increase of irisin, the lowest reduction in maximal voluntary contraction and specific force of Fiber Slow/1, the highest increase of FNDC5ge in adipose tissue, and no variation of FNDC5ge in skeletal muscle were recorded. Subjects who had the highest FNDC5ge in adipose tissue but not in muscle tissue showed the highest circulating irisin levels and could better withstand the harmful effect of BR.

Project description:BackgroundMuscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRPα), which leads to cachexia in mice and is associated with cachexia in patients with CKD.MethodsWe assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRPα and sought mediators of metabolic responses in muscle and adipose tissues of mice with either muscle-specific or adipose tissue-specific KO of SIRPα. Metabolic responses were confirmed in primary cultures of adipose cells.ResultsIn mice with CKD, SIRPα expression was increased in WAT (three-fold, P < 0.05), and this was associated with precursors of cachexia: 'pathologic browning', thermogenesis, and a two-fold activation of protein kinase A (P < 0.05 vs. control mice) plus loss of adipose tissue mass. In contrast, mice with SIRPα global KO and CKD or acute diabetes experienced improved insulin signalling and activation of pAkt plus 'physiologic browning' of WAT. These mice avoided losses of muscle and adipose tissues and experienced a 31% improvement in survival (P < 0.05) than did wild-type mice with CKD. In muscle-specific SIRPα KO mice with CKD, we uncovered that serum SIRPα levels (P < 0.05) were suppressed and were associated with improved insulin signalling both in skeletal muscles and in WAT. These changes were accompanied by physiologic WAT browning. However, in adipose-specific SIRPα KO mice with CKD, levels of serum SIRPα were increased over two-fold (P < 0.05), while muscle losses were minimally inhibited. Clinical implications of SIRPα signalling are suggested by our findings that include increased SIRPα expression in muscle and adipose tissues (P < 0.05 vs. healthy controls) plus higher SIRPα levels in the serum of patients with CKD (2.4-fold, P=0.000017 vs. healthy controls).ConclusionsOur results show that SIRPα plays an important role as an anti-insulin mediator regulating pathways to cachexia. In muscle-specific SIRPα KO, changes in SIRPα serum levels seem to improve insulin signalling in muscle and WAT, suggesting crosstalk between muscle and adipose tissue. Therefore, targeting SIRPα may prevent cachexia in patients with CKD or acute diabetes.

Project description:Irisin is an exercise-induced hormone that regulates lipid metabolism. The present study investigates whether the anti-obesity effect of the natural flavonoid pentamethylquercetin (PMQ) is related to irisin secretion from skeletal muscle in whole animals and cultured cells. Obese mice induced by monosodium glutamate were administered oral PMQ to determine blood irisin level and in vivo parameters of lipid metabolism, and cultured mouse C2C12 myoblasts and 3T3-L1 preadipocytes were employed to investigate the related molecular identities. PMQ increased circulating irisin and decreased bodyweight, insulin, and lipid levels accompanied with increasing brown-like adipocyte formation in obese mice. The brown adipocyte marker uncoupling protein 1 (UCP-1) and other brown-like adipocyte-specific genes and/or markers were increased in mouse white fat tissue, while PMQ treatment reversed the above changes. PMQ also dose-dependently increased the reduced levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and fibronectin type III domain-containing 5 (FNDC5) signal molecules in obese mice. Interestingly, the irisin level was increased in the culture medium of C2C12 cells treated with PMQ, and the conditioned medium stimulated the brown-like transition of 3T3-L1 preadipocytes with the increased expression of PGC-1α, FNDC5, UCP-1, and other brown-like adipocyte-specific genes. The effects of conditioned culture medium were abolished in C2C12 cells with silenced PGC-1α. On the other hand, PMQ-induced upregulation of PGC-1α and FNDC5 expression was reduced by AMPK inhibitor Compound C in C2C12 cells. Our results demonstrate the novel information that PMQ-induced irisin secretion from skeletal muscle involves the improvement of metabolic dysfunction in obese mice via activating the AMPK/PGC-1α/FNDC5 signal pathway, suggesting that PMQ modulates skeletal muscle-adipose tissue crosstalk and may be a promising drug candidate for treating obesity and obesity-related metabolic diseases.

Project description:Adipose tissue secretes numerous cytokines (termed 'adipokines') that have known or hypothesized actions on skeletal muscle. The majority of adipokines have been implicated in the pathological link between excess adipose and muscle insulin resistance, but approximately half also have documented in vitro effects on myogenesis and/or hypertrophy. This complexity suggests a potential dual role for adipokines in the regulation of muscle mass in homeostasis and the development of pathology. In this study, we used lipodystrophic 'fat-free' mice to demonstrate that adipose tissue is indeed necessary for the development of normal muscle mass and strength. Fat-free mice had significantly reduced mass (∼15%) and peak contractile tension (∼20%) of fast-twitch muscles, a slowing of contractile dynamics and decreased cross-sectional area of fast twitch fibres compared to wild-type littermates. These deficits in mass and contractile tension were fully rescued by reconstitution of ∼10% of normal adipose mass, indicating that this phenotype is the direct consequence of absent adipose. We then showed that the rescue is solely mediated by the adipokine leptin, as similar reconstitution of adipose from leptin-knockout mice fails to rescue mass or strength. Together, these data indicate that the development of muscle mass and strength in wild-type mice is dependent on adipose-secreted leptin. This finding extends our current understanding of the multiple roles of adipokines in physiology as well as disease pathophysiology to include a critical role for the adipokine leptin in muscle homeostasis. KEY POINTS: Adipose-derived cytokines (adipokines) have long been implicated in the pathogenesis of insulin resistance in obesity but likely have other under-appreciated roles in muscle physiology. Here we use a fat-free mouse to show that adipose tissue is necessary for the normal development of muscle mass and strength. Through add-back of genetically modified adipose tissue we show that leptin is the key adipokine mediating this regulation. This expands our understanding of leptin's role in adipose-muscle signalling to include development and homeostasis and adds the surprising finding that leptin is the sole mediator of the maintenance of muscle mass and strength by adipose tissue.

Project description:BackgroundThe relationship between intramuscular adipose tissue at admission and recovery of activities of daily living (ADL) remains unclear. This study aimed to examine the relationship between intramuscular adipose tissue in the quadriceps at admission and recovery of ADL in older inpatients.MethodsThis prospective study included 404 inpatients aged ≥65 years (54.7% female). Recovery of ADL during hospital stay was assessed using the Barthel Index (BI) score at discharge, BI score change, and BI efficiency. Higher BI at discharge, BI score change, and BI efficiency indicate more improvement in ADL. Intramuscular adipose tissue and muscle mass of the quadriceps were assessed using echo intensity and muscle thickness on ultrasound images, respectively. Multiple regression analysis was performed to identify factors independently associated with BI score at discharge, BI score change, and BI efficiency. The independent variables were BI score at admission, echo intensity and muscle thickness of the quadriceps, age, sex, number of medications, C-reactive protein concentration, updated Charlson Comorbidity Index score, Food Intake Level Scale, Geriatric Nutritional Risk Index score, days from onset disease, length of hospital stay, number of units of rehabilitation therapy, and subcutaneous fat thickness of the thigh.ResultsThe medians (inter-quartile range) of the BI score at discharge, BI score change, and BI efficiency were 60.0 (35.0-80.0), 10.0 (0.0-25.0), and 0.11 (0.00-0.37), respectively. The median (inter-quartile range) of the length of hospital stay (days) and days from onset disease were 58.0 (39.0-92.0) and 79.0 (49.0-112.0), respectively. Quadriceps echo intensity was independently and significantly associated with the BI score at discharge (β = -0.13, P < 0.01), BI score change (β = -0.23, P < 0.01), and BI efficiency (β = -0.21, P < 0.01). Quadriceps thickness was not independently and significantly associated with the BI score at discharge (β = -0.02, P = 0.68), BI score change (β = -0.02, P = 0.79), and BI efficiency (β = 0.03, P = 0.67).ConclusionsOur study indicates that greater intramuscular adipose tissue in the quadriceps at admission is more strongly related to worse recovery of ADL than less muscle mass in older inpatients. Greater intramuscular adipose tissue in the quadriceps in older inpatients is considered to be a predictor of worse recovery of ADL, and intervening for greater intramuscular adipose tissue may be important for improving ADL in older inpatients.

Dataset Information

Determinants of bone mass in older adults with normal- and overweight derived from the crosstalk with muscle and adipose tissue.

Publications

Determinants of bone mass in older adults with normal- and overweight derived from the crosstalk with muscle and adipose tissue.

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