Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels\' correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients\' age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials.

Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.

BACKGROUND: Chronic kidney disease is linked to a disturbed fibroblast growth factor-23 (FGF23)-Klotho axis and an imbalance between myostatin and insulin-like growth factor-1 (IGF-1) expression. This cross-sectional study investigates the association of the FGF23-Klotho axis and myokine profile with serum interleukin-6 (IL-6) and their interactions in pediatric patients.
METHODS: Serum calcium, phosphorus, 25-hydroxyvitamin D, parathormone, c-terminal FGF23, a-Klotho, myostatin, follistatin, IGF-1, and IL-6 were measured in 53 patients with GFR < 60 ml/min/1,73m2. Myostatin to lean mass (LM) and to IGF-1 ratios were calculated. IL-6 level > 3rd quartile was considered as high.
RESULTS: Myostatin, IGF-1, and follistatin were correlated to LM (rs = 0.513, p < 0.001, rs = 0.652, p < 0.001, rs=-0.483, p < 0.001). Myostatin and follistatin were correlated to IGF-1 (rs = 0.340, p = 0.014, rs=-0.385, p = 0.005). Myostatin/LM but not myostatin or myostatin/IGF-1 ratio was significantly higher in CKD 5D patients (p = 0.001,p = 0.844, p = 0.111). Among mineral bone parameters, lnFGF23 was correlated to lnIL-6 (rs = 0.397, p = 0.004) and associated with high IL-6 (OR 1.905, 95% CI 1.023-3.548). Among myokines, myostatin/IGF-1 ratio was correlated to lnIL-6 (rs = 0.395, p = 0.004) and associated with high IL-6 (OR 1.113, 95% CI 1.028-1.205). All associations were adjusted to CKD stage. Myostatin was correlated to lnFGF23 (rs = 0.331, p = 0.025) and myostatin/IGF-1 ratio to lnKlotho (rs=-0.363, p = 0.013), after adjustment for CKD stage, lnIL-6 and other mineral bone parameters.
CONCLUSIONS: In pediatric CKD, FGF23 and myostatin/IGF-1 ratio are associated with IL-6, indicating a link between systemic inflammation, mineral bone, and myokine disorders. The correlations between myostatin and FGF23 and between myostatin/IGF-1 and Klotho suggest an interaction between mineral bone and muscle metabolism.

UNASSIGNED: Exercise-induced cytokines involved in controlling body composition include myostatin (MST) and follistatin (FST), both of which are influenced by physical activity. This study investigated changes in body composition and physical activity during a weight loss program, as well as the impact on serum MST and FST levels at various weight loss rates.
UNASSIGNED: A total of 126 patients with obesity who completed a 6-month weight loss program were divided into three groups based on weight loss rate (%): low (< 3%), middle (3-10%), and high (≥10%). The International Physical Activity Questionnaire was used for assessing physical activity, whereas dual X-ray absorptiometry was used to determine body composition. Serum MST and FST levels were measured using the enzyme-linked immunosorbent assay.
UNASSIGNED: The middle and high groups showed a significant decrease in percent body fat and a significant increase in percent lean body mass and physical activity. Serum MST levels increased significantly in all three groups, although FST levels reduced significantly only in the middle group. After adjusting for sex and body composition, changes in peak oxygen intake (β = -0.359) and serum FST levels (β = -0.461) were identified as independent factors for the change in MST levels in the low group. Sex (β = -0.420) and changes in MST levels (β = -0.525) were identified as independent factors for the change in serum FST levels in the low group, whereas in the high group, sitting time (β = -0.600) during the weight loss program was identified as an independent factor for change in serum FST levels.
UNASSIGNED: Serum MST levels in patients with obesity increased significantly following the weight loss program, independent of weight loss rate. In contrast, serum FST levels reduced significantly only in the 3-10% weight loss group. These findings indicate that MST and FST secretion dynamics may fluctuate in response to physical activity, while also reflecting feedback regulation of body composition and metabolism during weight reduction.

The activins-follistatins-inhibins (AFI) hormonal system affects bone metabolism. Treatments that alter bone metabolism may also alter the AFI molecules. In this non-randomized, open-label, head-to-head comparative study, circulating levels of the AFI system were evaluated in postmenopausal women with osteoporosis treated for 12 mo with either teriparatide (n = 23) or denosumab (n = 22). Τeriparatide treatment increased activin B (P=.01) and activin AB (P=.004) and the ratios activin A/follistatin (P=.006), activin B/follistatin (P=.007), activin AB/follistatin (P<.001), and activin AB/ follistatin-like 3 (FSTL3) (P=.034). The significant P for trend in group × time interactions of activins B and AB and of the ratio activin AB/FSTL3 remained robust after adjustment for BMI and LS BMD but it was lost for activin B after adjustment for previous antiresorptive treatment. The effect of teriparatide on BMD was attenuated when it was adjusted for baseline activins levels or their 12-mo changes. No changes were observed after denosumab treatment. In conclusion, activins B and AB, as well as the ratios of all activins to follistatin and of activin AB to FSTL3 increased with teriparatide treatment, possibly in a compensatory manner. Future studies are needed to study the potentially important role activins may play in bone biology and any associations with the effect of teriparatide on BMD. Clinical Trials identifier: NCT04206618. ClinicalTrials.gov  https://clinicaltrials.gov/search?term=NCT04206618.
Bone and the muscle comprise 2 tissues that are considered to interact with each other, not only through mechanical but also through endocrine signals. Several components of the activins–follistatins–inhibins (AFI) hormonal system have been shown to be secreted by the muscle and affect the bone possibly contributing to this interplay. We have previously investigated the levels of the AFI molecules in case–control studies and reported differences between osteoporotic vs osteopenic vs postmenopausal and premenopausal women with normal BMD. In this 12-mo, non-randomized, open-labeled, head-to-head comparative study, we prospectively compared the effect of antiosteoporotic agents with opposite effect on bone metabolism, that is, teriparatide vs denosumab, on the circulating concentrations of all known molecules of the AFI system in postmenopausal women with osteoporosis. We observed increases of activins after teriparatide treatment, but no effect after denosumab treatment on any of the AFI molecules studied. Since activins are mainly acting in an autocrine way and since activin B and AB have not been extensively studied, further studies in the basic research, preclinical, and clinical research fields are required to expand these observations and fully elucidate physiology and any therapeutic potential.

OBJECTIVE: 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.
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).
CONCLUSIONS: 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.

Metabolically healthy obesity (MHO) refers to obese individuals with a favorable metabolic profile, without severe metabolic abnormalities. This study aimed to investigate the potential of follistatin, a regulator of metabolic balance, as a biomarker to distinguish between metabolically healthy and unhealthy obesity. This cross-sectional study included 30 metabolically healthy and 32 metabolically unhealthy individuals with obesity. Blood samples were collected to measure the follistatin levels using an enzyme-linked immunosorbent assay (ELISA). While follistatin did not significantly differentiate between metabolically healthy (median 41.84 [IQR, 37.68 to 80.09]) and unhealthy (median 42.44 [IQR, 39.54 to 82.55]) individuals with obesity (p = 0.642), other biochemical markers, such as HDL cholesterol, triglycerides, C-peptide, and AST, showed significant differences between the two groups. Insulin was the most significant predictor of follistatin levels, with a coefficient of 0.903, followed by C-peptide, which exerted a negative influence at -0.624. Quantile regression analysis revealed nuanced associations between the follistatin levels and metabolic parameters in different quantiles. Although follistatin may not serve as a biomarker for identifying MHO and metabolically unhealthy obesity, understanding the underlying mechanisms that contribute to metabolic dysfunction could provide personalized strategies for managing obesity and preventing associated complications.

Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with a risk associated with hormonal and reproductive factors. However, the potential causal effects between these factors and SLE remain unclear. A two-sample Mendelian randomization study was conducted using the published summary data from the genome-wide association study database. Five independent genetic variants associated with hormonal and reproductive factors were selected as instrumental variables: age at menarche, age at natural menopause, estradiol, testosterone, and follistatin. To estimate the causal relationship between these exposure factors and disease outcome, we employed the inverse-variance weighted, weighted median, and MR-Egger methods. In addition, we carried out multiple sensitivity analyses to validate model assumptions. Inverse variance weighted showed that there was a causal association between circulating follistatin and SLE risk (OR = 1.38, 95% CI 1.03 to 1.86, P = 0.033). However, no evidence was found that correlation between AAM (OR = 1.04, 95% CI 0.77 to 1.40, P = 0.798), ANM (OR = 0.99, 95% CI 0.92 to 1.06, P = 0.721), E2 (OR = 1.40, 95% CI 0.14 to 13.56, P = 0.772), T (OR = 1.25, 95% CI 0.70 to 2.28, P = 0.459), and SLE risk. Our study revealed that elevated circulating follistatin associates with an increased risk of SLE. This finding suggests that the regulatory signals mediated by circulating follistatin may provide a potential mechanism relevant to the treatment of SLE.

UNASSIGNED: Malnutrition and sarcopenia are common and impact the prognosis in patients with liver cirrhosis. The etiology is multifactorial and includes periods of reduced caloric intake, increased catabolism and direct molecular mechanisms that inhibit muscle synthesis. Although these conditions are widely acknowledged, and there is a growing interest in their diagnosis, robust evidence regarding the treatment and reversibility of these conditions is still lacking.
UNASSIGNED: We have explored the current evidence on the pharmacological treatment of sarcopenia in patients with cirrhosis. Additionally, we have searched for drugs already in use and ongoing trials for other chronic diseases.
UNASSIGNED: The current guidelines recommend the use of a protein-adequate diet and moderate physical activity for treating sarcopenia in patients with cirrhosis. Currently, robust evidence is derived only from the supplementation of Branched-Chain Amino Acids, capable of increasing muscle mass and function. There are many drugs targeting various pathways that contribute to sarcopenia. However, evidence is sporadic and insufficient to suggest their use in clinical practice.Novel drugs specifically designed to enhance muscle mass and function should be developed. Finally, gender significantly influences the type of muscle alteration and therapeutic mechanisms; therefore, future studies should be designed taking gender differences into consideration.

Activin A is known to impede tubular repair following renal ischemia, whereas exogenous follistatin, an activin A antagonist, has been shown to ameliorate kidney damage in rats. Despite these findings, the precise role of endogenous follistatin in the kidney has yet to be elucidated. In this study, we investigated the localization of follistatin in the normal human kidney and its potential utility as a marker for acute kidney injury (AKI). In a total of 118 AKI patients and 16 healthy adults, follistatin levels in serum and urine were quantified using ELISA, and correlations with clinical parameters were analyzed. Follistatin-producing cells were positive for Na-Cl co-transporter and uromodulin, but negative for aquaporin 1 and aquaporin 2. Unlike healthy adults, urinary follistatin significantly increased in AKI patients, correlating positively with AKI severity. Urinary follistatin levels were notably higher in patients needing renal replacement therapy. Significant correlations were observed with urinary protein, α1 microglobulin, and urinary NGAL, but not with urinary KIM-1, urinary L-FABP, urinary NAG, urinary β2 microglobulin, or serum creatinine. Interestingly, no correlation between urinary and serum follistatin levels was identified, indicating a renal origin for urinary follistatin. In conclusion, follistatin, produced by distal tubules, is detectable in the urine of AKI patients, suggesting its potential as a valuable marker for monitoring acute tubular damage severity in AKI.