A research group including Special Assistant Professor Muhammad Bilal and Special Research Professor Kazuyuki Tobe from the Research Center for Pre-Disease Science as well as Associate Professor Shiho Fujisaka and Professor Masaru Kato from the First Department of Internal Medicine, Faculty of Medicine, Academic Research Division, University of Toyama, revealed that TGF-β1 derived from anti-inflammatory CD206+ M2 macrophages is involved in the onset of skeletal muscle dysfunction (sarcopenic obesity) occurring in obesity. In an obesity model of mice with the same gene deleted, they confirmed that muscle atrophy was suppressed, adiponectin secretion from adipose tissue was increased, and mitochondrial function was improved. This indicates the potential to become a new therapeutic target for sarcopenia associated with obesity and type 2 diabetes. The results were published in the Journal of Cachexia, Sarcopenia and Muscle on June 18.
Obesity and type 2 diabetes adversely affect systemic tissues, including skeletal muscle, via systemic insulin resistance, dyslipidemia, chronic inflammation, and oxidative stress. In addition, obesity caused by a high-fat diet induces skeletal muscle atrophy, leading to decreases in muscle mass and motor function. In obese states, excess fat accumulates ectopic-wise not only in visceral adipose tissue but also in skeletal muscle, causing chronic inflammation and inducing "sarcopenic obesity," which is characterized by a general decline in physical function.
Macrophages, a type of immune cell, are known to be an important source of secreted factors such as cytokines that regulate myogenesis. After skeletal muscle injury, inflammatory M1 macrophages first accumulate and secrete factors that promote the proliferation and differentiation of muscle satellite cells. Next, anti-inflammatory M2 macrophages are thought to promote repair and regeneration, such as the remodeling of the extracellular matrix.
Previously, the research group reported that removing CD206+ M2 macrophages caused fibro-adipogenic progenitors (FAPs), which are mesenchymal progenitor cells present in skeletal muscle, to express follistatin (Fst: a protein that inhibits the action of myostatin and activin, promoting myogenesis and muscle hypertrophy), thereby promoting muscle repair. On the other hand, how macrophage-derived TGF-β1 affects skeletal muscle function under obese conditions was unknown.
Therefore, the research group generated mice with a specific deletion of the TGF-β1 gene in CD206+ M2 macrophages (TGF-β1 KO) and analyzed skeletal muscle function in a high-fat diet-induced obesity model.
As a result, FAPs in skeletal muscle were activated, and the expression of follistatin and follistatin-like protein 1 (Fstl1) increased. Through this, it was found to promote myogenesis. Furthermore, they clarified that it increased the secretion of adiponectin (a hormone secreted from adipose tissue that activates the AMPK pathway and improves glucose and lipid metabolism) from adipose tissue and activated the AMPK/SIRT1/PGC-1α signaling pathway, which regulates mitochondrial biogenesis and function in skeletal muscle, thereby improving mitochondrial function.
A decline in mitochondrial function is considered one of the major pathologies of sarcopenia. With the improvement in mitochondrial function and fatty acid oxidation capacity, exercise tolerance (running distance and running time), grip strength, and hanging time were significantly improved compared with the control group.
Tobe commented, "I was greatly surprised by the result that removing the M2 macrophage-derived TGF-β1 gene caused obese mice to run faster compared with control mice. Triggered by this discovery, a new relationship with skeletal muscle, not just glucose metabolism, has come into view. Moving forward, I hope to elucidate this mechanism in humans as well and develop this research toward treatments for sarcopenic obesity."
Journal Information
Publication: Journal of Cachexia, Sarcopenia and Muscle
Title: Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle
DOI: 10.1002/jcsm.70322
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