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.

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.

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.

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.

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.

BACKGROUND: Age-associated sarcopenia and declining physical function in older women are connected to changes in hormones, inflammation, and disrupted protein metabolism. Myokines and cytokines play central roles in muscle atrophy. While both resistance exercise (RE) and essential amino acid (EAA) supplementation are promising interventions, limited randomized trials have assessed their combined effect in healthy elderly populations. Early targeted strategies may help delay sarcopenia and promote healthier aging. METHODS: A 12-week randomized controlled trial was performed involving 96 healthy women aged ≥ 65 years without insulin resistance. Participants were randomized into four groups: control, RE, EAA, or RE + EAA. The intervention consisted of a circuit-based training program conducted three times per week, with each session lasting 60 minutes at moderate intensity. Participants in EAA and RE + EAA groups consumed 5.5g of EAA twice daily. Assessments before and after the intervention included body composition, muscle fitness, serum myokines, and inflammatory cytokines. Data analysis involved two-way repeated measures ANOVA, Bonferroni post-hoc comparisons, and one-way ANOVA for changes in the follistatin/myostatin ratio. RESULTS: The RE + EAA group demonstrated a significant increase in muscle mass (F(3, 72) = 5.042, p < 0.001, partial η² = 0.174) and greater improvements in the senior fitness test (p ranging from < 0.05 to < 0.001). There was a reduction in myostatin levels (p < 0.05) and an elevation in follistatin in both the RE (p < 0.05) and RE + EAA (p < 0.001) groups. The follistatin/myostatin ratio increased most in the RE + EAA group (F(3, 72) = 5.556, p = 0.002, partial η² = 0.188), with significance versus control (p < 0.001), EAA (p < 0.05) groups. IL-6 and IL-1β were significantly reduced in the RE (p < 0.05) and RE + EAA (p < 0.05) groups, whereas TNF-α decreased only in the RE + EAA group (p < 0.05). CONCLUSION: A 12-week intervention combining resistance exercise and essential amino acid supplementation was superior to either intervention alone in enhancing muscle mass, muscle fitness, myokine profiles, and reducing inflammatory markers among healthy older women. These results support the development of early combined interventions for the prevention of sarcopenia and may guide personalized exercise-nutrition prescriptions for optimal aging. TRIAL REGISTRATION: KCT 0010756 (Retrospectively registered; July 15, 2025).