Pathophysiology of sarcopenia: Genetic factors and their interplay with environmental factors.

Sarcopenia is a geriatric disorder characterized by a progressive decline in muscle mass and function. This disorder has been associated with a range of adverse health outcomes, including fractures, functional deterioration, and increased mortality. The pathophysiology of sarcopenia is highly complex and multifactorial, involving both genetic and environmental factors as key contributors. This review consolidates current knowledge on the genetic factors influencing the pathogenesis of sarcopenia, particularly focusing on the altered gene expression of structural and metabolic proteins, growth factors, hormones, and inflammatory cytokines. While the influence of environmental factors such as physical inactivity, chronic diseases, smoking, alcohol consumption, and sleep disturbances on sarcopenia is relatively well understood, there is a dearth of studies examining their mechanistic roles. Therefore, this review emphasizes the interplay between genetic and environmental factors, elucidating their cumulative role in exacerbating the progression of sarcopenia beyond their individual effects. The unique contribution of this review lies in synthesizing the latest evidence on the genetic factors and their interaction with environmental factors, aiming to inform the development of novel therapeutic or preventive interventions for sarcopenia.

Gasdermin D Deficiency Does Not Protect Mice from High-Fat Diet-Induced Glucose Intolerance and Adipose Tissue Inflammation.

The adipose tissue NLRP3 inflammasome has recently emerged as a contributor to obesity-related metabolic inflammation. Recent studies have demonstrated that the activation of the NLRP3 inflammasome cleaves gasdermin D (GSDMD) and induces pyroptosis, a proinflammatory programmed cell death. However, whether GSDMD is involved in the regulation of adipose tissue function and the development of obesity-induced metabolic disease remains unknown. The aim of the present study was to investigate the role of GSDMD in adipose tissue inflammation as well as whole-body metabolism using GSDMD-deficient mice fed a high-fat diet (HFD) for 30 weeks. The effects of GSDMD deficiency on adipose tissue, liver, and isolated macrophages from wild-type (WT) and GSDMD knockout (KO) mice were examined. In addition, 3T3-L1 cells were used to examine the expression of GSDMD during adipogenesis. The results demonstrate that although HFD-induced inflammation was partly ameliorated in isolated macrophages and liver, adipose tissue remained unaffected by GSDMD deficiency. Compared with the WT HFD mice, GSDMD KO HFD mice exhibited a mild increase in HFD-induced glucose intolerance with increased systemic and adipose tissue IL-1ß levels. Interestingly, GSDMD deficiency caused accumulation of fat mass when challenged with HFD, partly by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ). The expression of GSDMD mRNA and protein was dramatically suppressed during adipocyte differentiation and was inversely correlated with PPARγ expression. Together, these findings indicate that GSDMD is not a prerequisite for HFD-induced adipose tissue inflammation and suggest a noncanonical function of GSDMD in regulation of fat mass through PPARγ.

Associations of Circulating Irisin with FNDC5 Expression in Fat and Muscle in Type 1 and Type 2 Diabetic Mice.

Irisin is an exercise-induced myokine, suggested to exert beneficial effects on metabolism. However, the studies on the regulation of irisin secretion and the expression of its precursor FNDC5 have shown conflicting data. The discrepancies among previous correlation studies in humans are related to the heterogeneity of the study population. The fact that irisin is not only a myokine but also an adipokine leads to the further complexity of the role of irisin in metabolic regulation. In this study, we examined the regulation of FNDC5 expression and irisin in circulation in both type 1 and type 2 diabetic mice, and their potential relationships with metabolic parameters. In streptozotocin (STZ)-induced type 1 diabetic mice, high-fat diet (HFD)-induced obese mice and db/db mice, the circulating irisin as well as FNDC5 gene expression in subcutaneous fat was downregulated. Muscle FNDC5 expression was only significantly lower in STZ mice, and epididymal fat FNDC5 expression was unaltered. It is interesting to note that plasma irisin levels correlated positively with subcutaneous fat FNDC5 expression, but not epididymal fat or muscle. Moreover, both irisin levels and subcutaneous fat FNDC5 correlated negatively with markers of insulin resistance. These results suggest a regulatory role for subcutaneous fat-derived FNDC5/irisin in metabolic disease.

Irisin Exerts Inhibitory Effect on Adipogenesis Through Regulation of Wnt Signaling.

Irisin is an exercise-induced myokine known to induce adipocyte browning through induction of uncoupling protein 1. Recent studies have reported that irisin is also an adipokine. However, there is limiting evidence on the role of endogenous irisin from adipocytes. In this study we aim to elucidate the expression and secretion pattern of irisin during adipocyte differentiation and the role of endogenous and exogenous irisin on the adipogenic process. As such, recombinant irisin, plasmid expressing FNDC5 and small interfering RNA were utilized. Our results show that the gene expression of irisin precursor FNDC5 and irisin secretion increases at the early stage of adipogenesis. Both recombinant irisin treated cells and FNDC5-overexpressed cells resulted in inhibition of adipogenesis evidenced by downregulated C/EBPα, PPARγ, and FABP4 expression and reduced lipid accumulation. Further data showed that the inhibitory effect of irisin on adipogenesis is mediated though potentiation of Wnt expression, which is known to determine the fate of mesenchymal stem cells and regulate adipogenesis. Conversely, FNDC5 knockdown cells showed downregulated Wnt expression, but failed to further induce adipogenesis. This study suggests that both exogenous and endogenous irisin is able to inhibit adipogenesis and that activation of Wnt and subsequent repression of transcription factors is partly involved in this process. This provides a novel insight on the local effect of irisin on adipocytes and additional benefit to protect against obesity-related metabolic disorders.

The effects of phenolic glycosides from Betula platyphylla var. japonica on adipocyte differentiation and mature adipocyte metabolism.

Betula platyphylla var. japonica (Betulaceae) has been used traditionally in Asian countries for the treatment of inflammatory diseases. A recent study has reported a phenolic compound, platyphylloside from B. platyphylla, that shows inhibition on adipocyte differentiation and induces lipolysis in 3T3-L1 cells. Based on this finding, we conducted phytochemical analysis of the EtOH extract of the bark of B. platyphylla var. japonica, which resulted in the isolation of phenolic glycosides (1-4). Treatment of the isolated compounds (1-4) during adipocyte differentiation of 3T3-L1 mouse adipocytes resulted in dose-dependent inhibition of adipogenesis. In mature adipocytes, arylbutanoid glycosides (2-4) induced lipolysis related genes HSL and ATGL, whereas catechin glycoside (1) had no effect. Additionally, arylbutanoid glycosides (2-4) also induced GLUT4 and adiponectin mRNA expression, indicating improvement in insulin signaling. This suggests that the isolates from B. platyphylla var. japonica exert benefial effects in regulation of adipocyte differentiation as well as adipocyte metabolism.