Obesity has been linked to skeletal muscle loss and deterioration. While M2 macrophages may play a role in regulating muscle function, the underlying mechanisms remain poorly understood. Now, researchers from Japan have found that deleting the signaling protein transforming growth factor-beta 1 from a specific population of M2 macrophages protected mice from obesity-induced muscle dysfunction. This enhanced muscle regeneration and mitochondrial function, suggesting a potential therapeutic strategy for muscle loss associated with obesity. 

One of the many ways in which obesity harms the human body is through damage to skeletal muscle. This progressive muscle decline, also known as sarcopenia, reduces strength, mobility, and the ability to live independently. Unfortunately, most therapies for obesity and related conditions like type 2 diabetes focus solely on managing weight and blood glucose, rather than addressing the loss of muscle mass and function itself. Understanding what drives muscle deterioration during obesity and finding ways to reverse it are key to addressing this challenge.

In recent years, researchers have increasingly recognized that immune cells may help coordinate muscle regeneration by releasing signaling molecules that influence nearby cells. M2 macrophages, in particular, support muscle repair after injury by releasing signals that influence the growth and metabolism of nearby cells. Whether these same signals also contribute to the muscle loss associated with obesity, however, has remained unclear.

Now, a research team led by Distinguished Research Professor Kazuyuki Tobe of the Research Center for Pre-Disease Science at the University of Toyama, Japan, has addressed this knowledge gap. Their paper, published online in Volume 17, Issue 3 of the Journal of Cachexia, Sarcopenia and Muscle on June 18, 2026, reveals that deleting transforming growth factor-beta 1 (TGF-β1) from a specific subpopulation of M2 macrophages can protect skeletal muscle from obesity-induced dysfunction. Other members of the team included Dr. Muhammad Bilal and Dr. Shiho Fujisaka, also from the School of Medicine, University of Toyama.

The researchers engineered mice in which TGF-β1 could be deleted only in CD206+ M2 macrophages-the subpopulation of M2-type macrophages that express the CD206 surface receptor. After inducing TGF-β1 gene deletion, the mice were fed a high-fat diet for 12 weeks to produce obesity-related muscle dysfunction. The researchers then compared these knockout mice to control mice through several experiments, including running tests, grip strength and hanging tests, glucose and insulin tolerance tests, and detailed molecular analysis of muscle and fat tissue.

The knockout mice performed substantially better despite reaching similar body weights to control mice; they ran roughly twice as far before exhaustion, had greater grip strength, and could hang longer, while also exhibiting improved glucose tolerance and insulin sensitivity. In addition, the mice retained greater skeletal muscle mass, exhibited larger muscle fibers, and showed increased lean muscle mass, indicating protection against obesity-induced muscle wasting.

At the molecular level, the research team found two separate mechanisms potentially behind this improvement. First, loss of TGF-β1 activated fibro-adipogenic progenitors (FAPs), a population of muscle-resident support cells, which in turn increased expression of follistatin and follistatin-like protein 1. Both are known to promote new muscle fiber formation (myogenesis). Second, fat tissue in the knockout mice secreted more adiponectin, a hormone that activates the AdipoR1 receptor in muscle. This, in turn, switched on the AMPK/SIRT1/PGC-1α pathway, a core regulator of mitochondrial activity and energy metabolism in cells. "The activation of this pathway resulted in enhanced mitochondrial function and fatty acid oxidation, which translated to improved exercise performance observed in the engineered mice compared with control mice," explains Prof. Tobe. The researchers also observed reduced expression of fibrosis-related genes, suggesting that deletion of TGF-β1 may help preserve healthy muscle structure in addition to promoting regeneration.

Together, these findings show that TGF-β1 secreted by M2 macrophages contributes to obesity-associated muscle decline through two complementary mechanisms: one limiting muscle regeneration, the other impairing mitochondrial function. Blocking this single signal addressed both simultaneously, despite the knockout and control mice maintaining similar body weights throughout the study.

Although further studies will be needed before this approach can be translated to humans, the research team believes there is real potential for clinical applications in the future. "If the TGF-β1 gene in M2 macrophages could be removed in humans, older people with sarcopenia might regain muscle mass and become able to move more quickly and independently," remarks Prof. Tobe. With obesity-related muscle loss becoming increasingly common among aging populations worldwide, this work serves as a stepping stone towards a better quality of life for those affected by muscle dysfunction.

Source:

Journal reference:

Bilal, M., et al. (2026) Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle. Journal of Cachexia, Sarcopenia and Muscle. DOI: 10.1002/jcsm.70322. https://onlinelibrary.wiley.com/doi/10.1002/jcsm.70322