Follistatin

What Is Follistatin?

Follistatin (FST) represents a synthetic variant of the naturally occurring human follistatin protein. Follistatin exists in nearly all tissues of higher animals and manifests in two distinct isoforms resulting from alternative gene splicing. Its principal biological function involves inhibition of proteins in the TGF-beta superfamily. It demonstrates particularly potent neutralizing effects on activin, myostatin, and follicle-stimulating hormone.

Follistatin Effects

Follistatin research has been conducted by scientists who have shown that it inhibits myostatin, a protein that restricts muscle cell growth and differentiation. Myostatin represents one of the TGF-beta protein family and therefore is susceptible to inhibition by follistatin. Previous research has shown that genetic modification reducing or eliminating myostatin in animals results in dramatic muscle mass increases. Animals lacking functional myostatin develop exceptional muscle growth and strength, demonstrating the significant role myostatin plays in regulating muscle size and muscular equilibrium.

In mouse models, follistatin has been shown to increase lean muscle mass without the occurrence of fat tissue accumulation. After just seven weeks in follistatin-treated mice, muscle mass increased by 35%. Genetic modifications ensuring continuous follistatin expression led to muscle growth without accompanying fat gain, and also prevented age-related muscle mass decline.

Research is examining how follistatin enhances muscle size and development. There is hope that this protein can be used to treat muscle disorders, such as inclusion body myositis, for which there is no current effective treatment strategy. For instance, preclinical models of Duchenne muscular dystrophy have demonstrated that follistatin's introduction can substantially reduce disease progression and severity. Experiments indicate that muscle fiber could be protected and muscle function restored, offering hope to individuals with muscle-wasting diseases for which effective therapies do not currently exist.

Expanding lines of research into the effects of follistatin on muscle growth have found that gene administration of follistatin at any age can lead to long-lasting benefits including increased body mass. In mouse models, administration of follistatin via gene vector demonstrated remarkable increases in lifespan, cardiovascular function, and metabolic health. These benefits were observed regardless of the age of the animal at the time of gene therapy.

Research indicates that follistatin boosts muscle growth by stimulating muscle satellite cell regeneration. The protein may facilitate rapid tissue repair after injury, potentially shortening recovery periods. Investigations are ongoing to determine whether follistatin administration can enhance athletic performance, increase strength levels, or counteract age-related muscle decline (sarcopenia). Research indicates strong therapeutic potential for enhancing muscle mass and muscle strength, with skeletal muscle being the primary site of effects. Research additionally demonstrated that follistatin may counteract muscle decline caused by excessive activin signaling or muscle wasting.

Follistatin May Improve Survival in Breast Cancer

Research has found that higher follistatin levels correlate with improved survival outcomes in breast cancer patients. Follistatin concentrations have been measured using various techniques including reverse transcription polymerase chain reaction (RT-PCR) and enzyme immunoassay in tumor tissue. The findings indicate that low levels of follistatin correlated with poorer survival outcomes. The presence of follistatin correlated with better surviving breast cancer outcomes—the more follistatin production, the substantially better outcome and reduced mortality.

Follistatin's tumor inhibition effect involves blocking activin-signal-regulated pathways. These same factors play a significant role in breast cancer development and other disease states resulting in tumor growth. Additional investigations have found that follistatin blocks signals that lead to higher cell growth rates.

Research examined the mechanisms of tumor growth and demonstrated that biomarkers, among other substances, were measured in both mouse and human studies that found the ratio of follistatin expression within tumor tissue determined survival outcomes. In cancer settings, inhibition of activin and related TGF superfamily peptides via follistatin leads to improved outcomes.

Follistatin in Esophageal Cancer

Research has revealed that follistatin expression plays a role in the transition of normal esophageal tissue to Barrett's esophagus, a precursor to cancer. A research study investigated tissue samples obtained from patients with Barrett's esophagus and normal esophageal tissue to track expression changes.

While not mechanistically completely understood, scientists found a progression pattern in different cancers. For normal tissue transitions through Barrett's esophagus to adenocarcinoma development, multiple processes were sequentially characterized. These patterns indicate changes that may eventually lead to adverse developments.

Follistatin Research and Cancer Treatment

Investigations have discovered follistatin plays important roles in different cancers and that its effects are not limited to breast cancer. With lower concentrations detected in patients experiencing specific conditions, follistatin has been implicated across several types of diseases. Cancer studies reveal that follistatin may have wide applications for improved survival across various cancer types. Drug candidates targeting these pathways could potentially improve survival and reduce disease severity substantially.

Follistatin Associated with Cell Proliferation

Research in rats reveals that follistatin expression promotes cellular regrowth processes. Examinations discovered that after major liver surgery in rats where 70 percent of liver mass was removed, hepatic cells showed rapid follistatin expression to restore the organ. Hepatic cells produced follistatin expression following organ injury as a mechanism to accelerate normal growth. Five days following the procedure, there was documented elevated follistatin levels. There is a correlation between observed follistatin levels and faster regenerative processes for cellular and hepatic tissue recovery.

Follistatin Research and Liver Protection

Research shows follistatin functions as a defense mechanism against fibrosis and disease. In testing on mice, follistatin demonstrates a 75% reduction in fibrotic changes in mouse models where liver disease and fibrosis were induced. Liver fibrosis affects the progression of liver disease and cancer development.

Follistatin Provides Insight into Congenital Blindness

Investigations have discovered a link between follistatin and human vision development. It has been known that TGF-beta signaling is critical to developing eye structures. Further research showed follistatin controls activin signaling, which is critical for regulating bone architecture and biomechanics. However, many proteins can regulate bone activity, with follistatin acting as an inhibitor. Genetic tests reveal that lower follistatin expression, as occurs in genetic conditions, can lead to excessive bone growth that causes blindness stemming from bone overgrowth encroaching on eye function.

Follistatin Research and Hair Growth

Follistatin impacts hair development differently depending upon its localization. Laboratory work has shown follistatin deficiency causes reduced hair follicle growth. Measurements in mice showed decreased hair follicle production in follistatin-deficient models. While there is growing interest in reversing age-related hair loss, this represents a biologically-relevant area for follistatin research.

Follistatin Research and Insulin Deficiency and Diabetes

Follistatin demonstrates benefits in metabolic dysfunction through its impacts on muscle. Muscle tissue represents a major location of glucose storage and consumption. Increased muscle mass demonstrated improved health trends, diminished blood glucose levels, and decreased pathophysiological alterations. In research focused on diabetic rat models, the decline and pathology due to diabetes exhibited improvement, likely due to better-regulated muscle mass and strength. Research to evaluate metabolic conditions linked to follistatin is ongoing.

The Future of Follistatin Research

Follistatin research addresses numerous human conditions from cancer and muscle dysfunction to insulin resistance and diabetes. The field is very active, with new research consistently emerging due to the protein's wide-reaching capabilities. There is great potential in follistatin research, including possibilities for new clinical standards for a variety of illnesses and deficiencies.

Follistatin exhibits moderate side effects, but not widespread unfavorable impacts. Safety research has been more limited compared to some molecules. Follistatin is limited to educational and scientific research only, not for human consumption.

Article Author

The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.

Scientific Journal Author

Ruth A. Keri, Ph.D. Professor and Vice Chair at Department of Pharmacology in Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center Research. For more than 17 years, her research has focused on the genomic consequences of precocious puberty, endocrine therapy resistance, and mouse models of breast cancer. Her expertise in cell biologic models of cancer has contributed to over 100 peer-reviewed scientific findings detailing pathways contributing to aggressive cancer including vitamin D, autophagy, rapamycin, and other therapeutic targets in mammary cancer models. Most notably, she has published groundbreaking understanding of endocrine therapy resistance and hormone production by breast cancer epithelial cells and their potential resistance mechanisms. Her research includes analysis of proliferation and apoptosis, migration and invasion, and the efficacy of standard versus novel therapeutics. Her understanding of genome level expression changes and mechanisms that determine effects of drug treatment have led to many novel insights. She was the co-leader of the Cancer Progression Development in the Case Comprehensive Cancer Center, where she developed training programs for basic scientists seeking to advance in the field. She was recently awarded the Alumni Summit Mentor Award and the Ohio Women's Achievement Award.

Ruth A. Keri, Ph.D. is being referenced as one of the leading scientists involved in the research on the medicinal application of follistatin. She has been researching the translational applications of follistatin peptides for more than 10 years. The purpose of citing this doctor is to acknowledge, recognize and credit the educational insights created through biochemical medicinal properties research publications.

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