Follistatin

OBJECTIVES: The link between aging and pulmonary function decline is well-established, but the underlying mechanisms have yet to be fully revealed. Serum follistatin, a myokine implicated in muscle degeneration, may play a role in age-related pulmonary changes. This study aims to investigate the relationship between serum follistatin levels and pulmonary function decline in community-dwelling older adults, and evaluate their combined association with all-cause mortality. RESEARCH DESIGN AND METHODS: This longitudinal cohort study utilized data from 751 participants aged ≥50 years in the I-Lan Longitudinal Aging Study between 2018-2019. Serum follistatin levels, spirometry results, demographic and clinical data were retrieved. Participants were stratified based on their follistatin levels. Survival curves and group comparisons based on follistatin levels and decline in peak expiratory flow (PEF) using Kaplan-Meier analysis and log-rank tests. Multivariate Cox proportional hazards models were further used to identify independent predictors of all-cause mortality during the 52-month follow-up. RESULTS: Elevated follistatin levels significantly correlated with worse pulmonary function, particularly decreased PEF (p = 0.030). Kaplan-Meier analysis revealed the combination of elevated follistatin levels and decreased PEF was associated with increased risk of all-cause mortality (Log-rank p = 0.023). Cox proportional hazards models further identified that concurrent presence of higher follistatin levels and decreased PEF predicted higher risk of all-cause mortality (adjusted HR 3.58, 95% CI: 1.22-10.53, p = 0.020). CONCLUSION: Higher serum follistatin levels correlate with decreased pulmonary function, specifically PEF decline, in community-dwelling older adults. Furthermore, the coexistence of elevated follistatin levels and decreased PEF was associated with risk of all-cause mortality. Follistatin may serve as a biomarker for pulmonary aging and related adverse outcomes.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat obesity and metabolic diseases, yet their early impact on body composition and circulating regulators of muscle and bone remain unclear. This study aimed to assess early effects of liraglutide on total and regional body composition and associated changes in circulating markers of muscle and bone metabolism. METHODS: Twenty adults with obesity received liraglutide 3.0 mg/day or placebo for 35 days in this crossover randomized controlled trial. In this secondary analysis, body composition was assessed by dual-energy X-ray absorptiometry at the end of each phase, while hormones were measured by ELISA at baseline and at each of 6 weekly visits over 5 weeks. RESULTS: Liraglutide reduced body weight, BMI, and total and regional mass (trunk, hip, and extremities). Absolute fat-free mass was slightly but significantly lower. Absolute lean mass in the trunk and extremities decreased, whereas relative lean mass and fat-free mass percentages remained stable at treatment completion. CONCLUSIONS: Short-term liraglutide treatment reduces total and regional mass without altering relative body composition. Further research is warranted to confirm and clarify the clinical significance of these changes, to further study hormonal changes and identify strategies to preserve muscle mass during weight loss.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disorder that often leads to fatal outcomes, characterized by the aberrant proliferation of myofibroblasts and excessive deposition of extracellular matrix (ECM) components. Follistatin-like 1 (Fstl1), a secreted glycoprotein regulated by transforming growth factor β1 (TGF-β1), has been found to be markedly elevated in the fibrotic lungs of both patients with IPF and mice subjected to bleomycin-induced injury. Studies have shown that Fstl1 haploinsufficiency protects against bleomycin-induced lung injury, implicating Fstl1 as a potential therapeutic target. Here, we investigated the effect of Fstl1 knockdown using small interfering RNA (siRNA) on pulmonary fibrosis in vivo. METHODS: We designed four siRNA sequences targeting Fstl1 and evaluated their efficiency in mouse embryonic fibroblasts (MEFs). Of these, si-Fstl1-12 achieved maximal Fstl1 knockdown (∼80%) and significantly inhibited TGF-β1-induced upregulation of Fstl1 and ECM proteins in vitro. We used biodegradable poly (D, L-lactic-co-glycolic acid) (PLGA) nanomaterials as carriers for in vivo delivery. Bleomycin-treated mice were administered PLGA-si-Fstl1-12, and lung tissues were analyzed for Fstl1 expression, fibrosis severity, and collagen deposition. RESULTS: si-Fstl1-12 markedly suppressed TGF-β1-induced Fstl1 expression and ECM protein synthesis in MEFs in vitro. Treatment with PLGA-si-Fstl1-12 effectively reduced Fstl1 levels in lung tissue, attenuated interstitial fibrosis, and decreased collagen accumulation in bleomycin-challenged mice. Notably, even low doses of PLGA-si-Fstl1-12 achieved significant therapeutic effects, demonstrating efficient and safe siRNA delivery in vivo. CONCLUSIONS: Targeted Fstl1 inhibition using siRNA significantly mitigated pulmonary fibrosis in a murine bleomycin model. The successful application of PLGA nanomaterials for siRNA delivery underscores their potential for safe and effective in vivo gene silencing. These findings highlight si-Fstl1 as a promising therapeutic candidate for IPF and support further investigation of RNA-based nanomedicine in fibrotic lung diseases.

The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04-1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09-1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein known for its role in inflammation. However, plasma FSTL1 levels in patients with coronary artery disease (CAD) have not been fully elucidated. Thus, in this study, we investigated the plasma FSTL1 levels of 350 patients who underwent elective coronary angiography. The severity of CAD was represented as the numbers of > 50% stenotic vessels and segments and the severity score. CAD was detected in 196 patients, of whom 84 had 1-vessel disease (1-VD), 62 had 2-VD, and 50 had 3-VD. Plasma high-sensitivity C-reactive protein (hsCRP) levels were higher in patients with CAD than in those without CAD (median 0.56 versus 0.44 mg/L, P < 0.01). Notably, plasma FSTL1 levels were higher in patients with CAD than in those without CAD (median 4.05 versus 3.47 ng/mL, P < 0.02). A stepwise increase in FSTL1 levels was found depending on the number of > 50% stenotic vessels: 3.47 in CAD (-), 3.74 in 1-VD, 4.42 in 2-VD, and 4.65 ng/mL in 3-VD (P < 0.05). FSTL1 levels also correlated with the number of > 50% stenotic segments and the severity score (r = 0.14 and r = 0.15, respectively, P < 0.005) and hsCRP levels (r = 0.10, P < 0.05). In the multivariate analysis, FSTL1 levels were an independent factor associated with CAD. The odds ratio for CAD was 1.61 (95% CI = 1.01-2.58) for high FSTL1 level of > 3.6 ng/mL (P < 0.05). In conclusion, plasma FSTL1 levels in patients with CAD were found to be high and associated with the presence and severity of CAD, thus, suggesting that FSTL1 may play a role in the progression of coronary atherosclerosis.

INTRODUCTION: Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia, systemic inflammation, and metabolic dysfunction. Current diagnostic standards rely on polysomnography (PSG), which is limited by cost and accessibility. The identification of a sensitive and specific biomarker has the potential to aid both diagnosis and treatment monitoring. Follistatin-like 1 (FSTL1) has been implicated in inflammatory pathways; however, its role in OSA remains largely unexplored. MATERIALS AND METHODS: In this study, we aimed to explore changes in circulating FSTL1 levels in individuals with OSA to assess alterations following multilevel sleep surgery (MLS). We also evaluated its association with various metabolic and hypoxia-related markers, including Orexin-A, TNF-α, and IGFBP4. Our study was conducted at Dasman Diabetes Institute (DDI) in Kuwait through a cohort of 164 individuals, comprising 124 patients with OSA and 40 participants as non-OSA controls. Participants with OSA underwent MLS as a corrective intervention. A Type I polysomnography (PSG) test was performed in a level 1 sleep laboratory to diagnose sleep apnea. The apnea-hypopnea index (AHI) was measured at baseline and 3 months post-surgery to evaluate improvement in their condition. RESULTS: Circulating FSTL1 levels were significantly lower in individuals with OSA (10,245.53 ± 174.94; p < 0.001) compared to the control group (13,783.33 ± 688.69), with levels restored following surgery. Our data presented an inverse association between FSTL1 and AHI (p < 0.001), highlighting its potential use in reflecting OSA severity. Additionally, FSTL1 levels showed a significant negative correlation with the hypoxia-related marker IGFBP4 in OSA participants (r = -0.440; p = 0.005), suggesting a potential link to hypoxic regulation. FSTL1 levels increased significantly (p = 0.041) following MLS, coinciding with improvements in AHI and indicating remission of OSA. Further, the receiver operating curve (ROC) analysis emphasized a potential role for FSTL1 as a biomarker with predictive qualities for OSA, showing moderate diagnostic accuracy (AUC 0.73, 95% CI: 0.64-0.83, p < 0.001; 8819.09; sensitivity of 86.4%, specificity of 76.2%). CONCLUSION: FSTL1 demonstrates potential as a valuable biomarker that can aid current diagnostic tools for OSA and help evaluate treatment efficacy; however, additional research is warranted to confirm its clinical applicability and explore its therapeutic potential.