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Journal of Pharmacological Sciences 2014Skeletal muscle plays a key role in postural retention as well as locomotion for maintaining the physical activities of human life. Skeletal muscle has a second role as... (Review)
Review
Skeletal muscle plays a key role in postural retention as well as locomotion for maintaining the physical activities of human life. Skeletal muscle has a second role as an elaborate energy production and consumption system that influences the whole body's energy metabolism. Skeletal muscle is a specific organ that engenders a physical force, and exercise training has been known to bring about multiple benefits for human health maintenance and/or improvement. The mechanisms underlying the improvement of the human physical condition have been revealed: skeletal muscle synthesizes and secretes multiple factors, and these muscle-derived factors, so-called as myokines, exert beneficial effects on peripheral and remote organs. In this short review, we focus on the third aspect of skeletal muscle function - namely, the release of multiple types of myokines, which constitute a broad network for regulating the function of remote organs as well as skeletal muscle itself. We conclusively show that skeletal muscle is one of the endocrine organs and that understanding the mechanisms of production and secretion of myokines may lead to a new pharmacological approach for treatment of clinical disorders.
Topics: Activins; Adipokines; Bone Morphogenetic Proteins; Brain-Derived Neurotrophic Factor; Collagen; Energy Metabolism; Exercise; Fibronectins; Follistatin; Humans; Inhibins; Interleukins; Muscle, Skeletal; Myostatin; Transforming Growth Factor beta
PubMed: 24859778
DOI: 10.1254/jphs.14r02cp -
Proceedings of the National Academy of... May 2022As the global elderly population grows, it is socioeconomically and medically critical to provide diverse and effective means of mitigating the impact of aging on human...
As the global elderly population grows, it is socioeconomically and medically critical to provide diverse and effective means of mitigating the impact of aging on human health. Previous studies showed that the adeno-associated virus (AAV) vector induced overexpression of certain proteins, which can suppress or reverse the effects of aging in animal models. In our study, we sought to determine whether the high-capacity cytomegalovirus vector (CMV) can be an effective and safe gene delivery method for two such protective factors: telomerase reverse transcriptase (TERT) and follistatin (FST). We found that the mouse cytomegalovirus (MCMV) carrying exogenous TERT or FST (MCMVTERT or MCMVFST) extended median lifespan by 41.4% and 32.5%, respectively. We report CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity. Specifically, this treatment significantly improved glucose tolerance, physical performance, as well as preventing body mass loss and alopecia. Further, telomere shortening associated with aging was ameliorated by TERT and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects. Translating this research to humans could have significant benefits associated with quality of life and an increased health span.
Topics: Administration, Inhalation; Animals; Cytomegalovirus Infections; Follistatin; Genetic Therapy; Genetic Vectors; Injections, Intraperitoneal; Life Expectancy; Mice; Models, Animal; Neoplasms; Telomerase
PubMed: 35537048
DOI: 10.1073/pnas.2121499119 -
Nature Communications Nov 2022Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the...
Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206 M2-like macrophages and FAPs during the recovery process using a transgenic mouse model. Depletion of CD206 M2-like macrophages or deletion of CD206 M2-like macrophages-specific TGF-β1 gene induces myogenesis and muscle regeneration. We show that depletion of CD206 M2-like macrophages activates FAPs and activated FAPs secrete follistatin, a promyogenic factor, thereby boosting the recovery process. Conversely, deletion of the FAP-specific follistatin gene results in impaired muscle stem cell function, enhanced fibrosis, and delayed muscle regeneration. Mechanistically, CD206 M2-like macrophages inhibit the secretion of FAP-derived follistatin via TGF-β signaling. Here we show that CD206 M2-like macrophages constitute a microenvironment for FAPs and may regulate the myogenic potential of muscle stem/satellite cells.
Topics: Animals; Mice; Adipogenesis; Follistatin; Macrophages; Mice, Transgenic; Muscles; Mannose Receptor
PubMed: 36411280
DOI: 10.1038/s41467-022-34191-y -
Prostaglandins & Other Lipid Mediators Dec 2023Follistatin (FST) is a glycoprotein which main role is antagonizing activity of transforming growth factor β superfamily members. Folistatin-related proteins such as... (Review)
Review
Follistatin (FST) is a glycoprotein which main role is antagonizing activity of transforming growth factor β superfamily members. Folistatin-related proteins such as follistatin-like 3 (FSTL3) also reveal these properties. The exact function of them has still not been established, but it can be bound to the pathogenesis of metabolic disorders. So far, there were performed a few studies about their role in type 2 diabetes, obesity or gestational diabetes and even less in type 1 diabetes. The outcomes are contradictory and do not allow to draw exact conclusions. In this article we summarize the available information about connections between follistatin, as well as follistatin-like 3, and metabolic disorders. We also emphasize the strong need of performing further research to explain their exact role, especially in the pathogenesis of diabetes and obesity.
Topics: Humans; Follistatin; Diabetes Mellitus, Type 2; Obesity; Transforming Growth Factor beta
PubMed: 37739334
DOI: 10.1016/j.prostaglandins.2023.106785 -
Andrology Sep 2019The interface between the epididymis and the immune system is implicated in many male reproductive pathologies. The resident immune cell populations and... (Review)
Review
BACKGROUND
The interface between the epididymis and the immune system is implicated in many male reproductive pathologies. The resident immune cell populations and immune-environment within the epididymis are significantly different from the testis, which is an immune-privileged site. Moreover, the immune cell subsets and immunological responses between different regions of the epididymis vary considerably. The cauda epididymis is more susceptible to autoimmune responses than the caput in rodent models of active immunization or suppressed immune tolerance, and in men with congenital or physical damage to the reproductive tract. Activins are members of the transforming growth factor-β family of cytokines that are crucial for testis and epididymal development; however, they also have complex immunoregulatory properties and may play an essential role in the regulation of immunity in the reproductive tract.
MATERIALS AND METHODS
Our recent research and relevant publications by other researchers identified following a PubMed search are reviewed.
RESULTS
The caput epididymis displays elevated endogenous expression of activins A and B and the immunoregulatory gene, indoleamine-2,3-dioxygenase, co-existing with an extensive population of intra-epithelial and interstitial macrophages and dendritic cells, which appear to be involved in regulating tolerance against sperm antigens. The caput is also relatively resistant to inflammatory damage caused by autoimmunity or bacterial infection, but the cauda, which exhibits low activin expression and high levels of the activin-binding protein, follistatin, is highly susceptible to inflammatory damage. Paradoxically, inflammation in the cauda induces increased activin production, and inhibition of activin activity reduces inflammatory responses. Studies using mouse models with altered levels of activins and follistatin indicate a relationship between the activins and genes involved in inflammation and immunoregulation.
CONCLUSION
The existing data indicate that activins play a complex role in controlling inflammation and immunity in the epididymis and vas deferens.
Topics: Activins; Animals; Epididymis; Epididymitis; Follistatin; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inhibin-beta Subunits; Inhibins; Male; Mice; Models, Animal; Vas Deferens
PubMed: 31322318
DOI: 10.1111/andr.12682 -
Nature Communications Jan 2023Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains...
Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains unknown. Here we show, using an orthotopic murine lung cancer model and human carcinoma samples, that AMs support cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of activin A, a homodimer of INHBA. Accordingly, follistatin, an antagonist of activin A is able to inhibit lung cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBA/activin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts.
Topics: Humans; Animals; Mice; Macrophages, Alveolar; Activins; Follistatin; Lung; Lung Neoplasms; Carcinoma
PubMed: 36650150
DOI: 10.1038/s41467-022-35701-8 -
Science Advances Feb 2022Hair cell (HC) loss within the inner ear cochlea is a leading cause for deafness in humans. Before the onset of hearing, immature supporting cells (SCs) in neonatal mice...
Hair cell (HC) loss within the inner ear cochlea is a leading cause for deafness in humans. Before the onset of hearing, immature supporting cells (SCs) in neonatal mice have some limited capacity for HC regeneration. Here, we show that in organoid culture, transient activation of the progenitor-specific RNA binding protein LIN28B and Activin antagonist follistatin (FST) enhances regenerative competence of maturing/mature cochlear SCs by reprogramming them into progenitor-like cells. Transcriptome profiling and mechanistic studies reveal that LIN28B drives SC reprogramming, while FST is required to counterbalance hyperactivation of transforming growth factor-β-type signaling by LIN28B. Last, we show that LIN28B and FST coactivation enhances spontaneous cochlear HC regeneration in neonatal mice and that LIN28B may be part of an endogenous repair mechanism that primes SCs for HC regeneration. These findings indicate that SC dedifferentiation is critical for HC regeneration and identify LIN28B and FST as main regulators.
Topics: Animals; Cellular Reprogramming; Cochlea; Follistatin; Hair Cells, Auditory; Mice; Regeneration
PubMed: 35148175
DOI: 10.1126/sciadv.abj7651 -
Clinical and Molecular Hepatology Sep 2019Sarcopenia (loss of muscle mass and/or strength) frequently complicates liver cirrhosis and adversely affects the quality of life; cirrhosis related liver decompensation... (Review)
Review
Sarcopenia (loss of muscle mass and/or strength) frequently complicates liver cirrhosis and adversely affects the quality of life; cirrhosis related liver decompensation and significantly decreases wait-list and post-liver transplantation survival. The main therapeutic strategies to improve or reverse sarcopenia include dietary interventions (supplemental calorie and protein intake), increased physical activity (supervised resistance and endurance exercises), hormonal therapy (testosterone), and ammonia lowering agents (L-ornithine L-aspartate, branch chain amino acids) as well as mechanistic approaches that target underlying molecular and metabolic abnormalities. Besides other factors, hyperammonemia has recently gained attention and increase sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Sarcopenia contributes to frailty and increases the risk of minimal and overt hepatic encephalopathy.
Topics: Ammonia; Exercise Therapy; Follistatin; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Muscle Proteins; Muscle, Skeletal; Sarcopenia; Testosterone
PubMed: 31006226
DOI: 10.3350/cmh.2019.0015 -
Mediators of Inflammation 2015Pegylated-interferon-α based therapy for the treatment of chronic hepatitis C (CHC) is considered suboptimal as not all patients respond to the treatment and it is... (Review)
Review
Pegylated-interferon-α based therapy for the treatment of chronic hepatitis C (CHC) is considered suboptimal as not all patients respond to the treatment and it is associated with several side effects that could lead to dose reduction and/or termination of therapy. The currently used markers to monitor the response to treatment are based on viral kinetics and their performance in the prediction of treatment outcome is moderate and does not combine accuracy and their values have several limitations. Hence, the development of new sensitive and specific predictor markers could provide a useful tool for the clinicians and healthcare providers, especially in the new era of interferon-free therapy, for the classification of patients according to their response to the standard therapy and only subscribing the novel directly acting antiviral drugs to those who are anticipated not to respond to the conventional therapy and/or have absolute contraindications for its use. The importance of activins and follistatin in the regulation of immune system, liver biology, and pathology has recently emerged. This review appraises the up-to-date knowledge regarding the role of activins and follistatin in liver biology and immune system and their role in the pathophysiology of CHC.
Topics: Activins; Follistatin; Hepatitis C, Chronic; Humans; Interferon-alpha
PubMed: 25969625
DOI: 10.1155/2015/287640 -
Pathology Oncology Research : POR 2021This study explored the roles of activins and follistatin in colorectal cancers. Paired malignant and normal colonic tissues were collected from archived...
This study explored the roles of activins and follistatin in colorectal cancers. Paired malignant and normal colonic tissues were collected from archived paraffin-embedded ( = 90 patients) alongside fresh ( = 40 patients) specimen cohorts. Activin β-subunits, follistatin and Smad4 mRNAs and proteins were measured by real-time PCR and immunohistochemistry (IHC). Mature activin-A, -B, -AB and follistatin proteins were measured by ELISA. Cancer tissues having ≤ the 20th percentile of the Smad4 IHC score were considered as low (L-S4) group. The Smad4-intact SW480 and Smad4-null HT29 colon cancer cell lines were treated with activins and follistatin, and cell cycle was analysed by flow cytometry. The cell cycle inducing (CCND1/CCND3) and inhibitory (p21/p27) proteins alongside the survival (survivin/BCL2) and pro-apoptosis (Casp-8/Casp-3) markers were measured by immunofluorescence. Thirty-nine patients had right-sided cancers (30%) and showed higher rates of L-S4 tumours ( = 17; 13.1%) alongside worse clinicopathological characteristics relative to left-sided cancers. The βA-subunit and activin-A increased, whilst βB-subunit and activin-AB decreased, in malignant sites and the late-stage cancers revealed the greatest abnormalities. Interestingly, follistatin declined markedly in early-stage malignant tissues, whilst increased significantly in the advanced stages. All activin molecules were comparable between the early stage right- and left-sided tumours, whereas the late-stage right-sided cancers and L-S4 tumours showed more profound deregulations. , activin-A increased the numbers of the SW480 cells in sub-G1 and G0/G1-phases, whereas reduced the HT29 cell numbers in the sub-G1 phase with simultaneous increases in the G0/G1 and S phases. The p21/p27/Casp-8/Casp-3 proteins escalated, whilst CCND1/CCND3/BCL2/survivin declined in the SW480 cells following activin-A, whereas activin-A only promoted p21 and p27 alongside reduced CCND3 in the HT29 cells. By contrast, activin-AB increased the numbers of SW480 and HT29 cells in Sub-G1 and G0/G1-phases and promoted the anti-cancer and reduced the oncogenic proteins in both cell lines. In conclusion, activins and follistatin displayed stage-dependent dysregulations and were markedly altered during the advanced stages of right-sided and L-S4 cancers. Moreover, the activin-A actions in CRC could be Smad4-dependent, whereas activin-AB may act as a Smad4-independent tumour suppressor protein.
Topics: Activins; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Colorectal Neoplasms; Disease Progression; Female; Follistatin; Humans; Inhibin-beta Subunits; Male; RNA, Messenger; Smad4 Protein
PubMed: 34867090
DOI: 10.3389/pore.2021.1610032