Denervation occurs when the connection between a motor neuron and a muscle fiber is disrupted. Without regular electrical and chemical signals from the nervous system, muscle fibers lose contractile activity, alter their metabolism and progressively shrink. This process can follow traumatic nerve damage, spinal cord injury, peripheral neuropathy or certain neurological diseases. Although rehabilitation and surgical repair may restore function in some cases, muscle atrophy can advance before nerve connections are re-established, limiting recovery even when the original injury is treated.

The immune response to denervation is complex. Neutrophils are among the first cells recruited to damaged tissue, where they can destroy microbes, remove cellular debris and release signaling molecules. They are often associated with acute inflammation, but their effects are not exclusively destructive. The new study focuses on a neutrophil population identified by the surface markers CD11b and Ly6G. These cells appear to release S100A8 and S100A9, two calcium-binding proteins that act outside cells as inflammatory and tissue-regulating signals.

S100A8 and S100A9 are frequently produced in response to tissue stress and injury. They can form a protein complex known as calprotectin and influence the behavior of neighboring immune cells through pattern-recognition and inflammatory signaling pathways. In the denervated muscle examined by the researchers, the proteins were linked to the activation of a macrophage state associated with repair rather than prolonged tissue damage. This suggests that signals initially released during inflammation can help redirect the immune environment toward restoration.

The macrophages highlighted in the study were characterized as MerTK-high and Ly6C-low cells. MerTK, or MER receptor tyrosine kinase, is a receptor involved in the recognition and removal of dying cells, a process called efferocytosis. Clearing dead cells is essential because their remains can continue to provoke inflammation if they accumulate. Ly6C-low macrophages are generally associated with a more mature, tissue-supportive phenotype, although macrophage identities exist along a continuum rather than in rigid categories.

According to the researchers, S100A8 and S100A9 released by CD11b-positive, Ly6G-positive neutrophils help activate these MerTK-high, Ly6C-low reparative macrophages. The macrophages may then create a local environment that is more favorable to tissue maintenance, limiting the extent of muscle wasting after denervation. The proposed mechanism does not imply that neutrophils directly restore nerve function. Instead, it indicates that they can influence how muscle responds during the vulnerable period when neural input is absent.

This finding is significant because it challenges a simple view of inflammation as a uniformly harmful force in muscle injury. The timing, intensity and cellular source of inflammatory signals can determine whether they promote damage or recovery. S100A8 and S100A9 are known to participate in inflammatory diseases when their activity becomes excessive or persistent. In the context of denervated muscle, however, the study suggests that a controlled neutrophil-derived signal may support a beneficial transition in macrophage behavior.

The work also offers a possible explanation for why immune-cell composition matters during muscle degeneration. Two tissues with similar levels of nerve damage might undergo different degrees of atrophy if their neutrophils and macrophages respond differently. A treatment designed to preserve or reproduce the S100A8/S100A9 signal could potentially help maintain muscle tissue while nerve repair proceeds. Conversely, indiscriminately blocking these proteins might remove a signal that supports repair, even though suppressing inflammation could appear attractive at first.

Any therapeutic translation will require caution. S100A8 and S100A9 can contribute to harmful inflammation in other settings, and manipulating them systemically could affect infection control, autoimmune activity or cardiovascular health. Future studies will need to define the precise receptors and intracellular pathways through which the proteins influence reparative macrophages, determine how long the signal remains beneficial and establish whether the mechanism operates similarly in different muscles, disease models and human patients. Researchers will also need to distinguish effects on muscle fibers from effects on blood vessels, connective tissue and nerve regeneration.

For now, the study presents denervated muscle as an active immunological environment rather than a passive victim of lost nerve signals. Neutrophils and macrophages appear to participate in a coordinated sequence: early immune cells release S100A8 and S100A9, while a MerTK-high, Ly6C-low macrophage population responds with tissue-supportive activity. By revealing this cellular conversation, the research points toward therapies that do more than suppress inflammation—therapies that could selectively reshape it to preserve muscle until neural function can return.

Subject of Research: Neutrophil–macrophage communication and immune regulation of denervated muscle atrophy

Article Title: S100A8/S100A9 released by CD11b⁺Ly6G⁺ neutrophils activate MerTK^hiLy6c^lo reparative macrophages to delay denervated muscle atrophy

Article References: Xiang, Y., Zhu, L., Qiu, Z. et al. “S100A8/S100A9 released by CD11b⁺Ly6G⁺ neutrophils activate MerTK^hiLy6c^lo reparative macrophages to delay denervated muscle atrophy.” Experimental & Molecular Medicine (2026). https://doi.org/10.1038/s12276-026-01813-0

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01813-0

Keywords: denervation, muscle atrophy, neutrophils, macrophages, S100A8, S100A9, MerTK, Ly6C, immune regulation, tissue repair

The research, led by Distinguished Research Professor Kazuyuki Tobe at the University of Toyama’s Research Center for Pre-Disease Science, focuses on CD206-positive M2 macrophages. Macrophages are immune cells that respond to injury, inflammation, and changes in tissue metabolism. M2 macrophages are generally associated with tissue repair and remodeling, including the recovery of injured muscle. However, the new findings indicate that these cells may become harmful in the metabolic environment created by obesity by releasing excessive amounts of transforming growth factor-beta 1, or TGF-β1.

TGF-β1 is a powerful signaling molecule involved in cell growth, tissue remodeling, immune regulation, and fibrosis. In healthy amounts, it contributes to normal repair processes. But persistent or excessive TGF-β1 activity can alter the behavior of muscle-resident cells, promote scar-like tissue formation, and interfere with regeneration. To determine whether macrophage-derived TGF-β1 was directly involved in obesity-associated muscle dysfunction, the researchers created genetically engineered mice in which the Tgf-β1 gene could be selectively deleted in CD206-positive M2 macrophages.

The animals were then fed a high-fat diet for 12 weeks, a standard experimental approach for inducing obesity and metabolic dysfunction in mice. The researchers compared the modified animals with control mice that retained TGF-β1 production in the targeted macrophage population. Their analysis included endurance running, grip-strength testing, hanging tests, glucose and insulin tolerance assessments, and molecular examination of muscle and adipose tissue. The design allowed the team to distinguish the effects of macrophage-specific TGF-β1 deletion from the effects of body weight alone.

The results were striking. Although the modified and control mice reached similar body weights, the animals lacking TGF-β1 in CD206-positive M2 macrophages performed considerably better in physical tests. They ran approximately twice as far before exhaustion, demonstrated stronger grip, and remained suspended for longer during hanging tests. They also showed improved glucose tolerance and insulin sensitivity, suggesting that the intervention protected not only muscle performance but also broader metabolic function.

Measurements of body composition and muscle tissue provided a biological explanation for the improved performance. The modified mice retained more skeletal muscle, possessed larger muscle fibers, and had a greater proportion of lean mass than the control animals. These findings point to protection from obesity-induced muscle wasting rather than simply an improvement in motivation or exercise capacity. The muscle tissue also showed lower expression of genes linked to fibrosis, indicating that the absence of macrophage-derived TGF-β1 may help preserve the structural environment required for effective regeneration.

The researchers identified two interconnected mechanisms behind the protective effect. First, removing TGF-β1 activated fibro-adipogenic progenitors, or FAPs, which are support cells located within skeletal muscle. FAPs can influence the formation and repair of muscle fibers, although abnormal activation can also contribute to fibrosis. In this study, the altered FAP response was associated with increased production of follistatin and follistatin-like protein 1, molecules that support myogenesis—the process through which muscle precursor cells develop into new muscle fibers. This suggests that TGF-β1 normally restrains a regenerative program in the obese muscle environment.

The second mechanism involved communication between fat tissue and muscle. Adipose tissue from the modified mice released more adiponectin, a hormone with important effects on energy metabolism and insulin sensitivity. Adiponectin activated the AdipoR1 receptor in skeletal muscle, triggering the AMPK/SIRT1/PGC-1α signaling pathway. This pathway is a central regulator of mitochondrial biogenesis, fatty-acid oxidation, and cellular energy production. By increasing activity through this system, the muscle cells were better able to use fatty acids as fuel and maintain mitochondrial performance. The researchers connect this metabolic improvement to the enhanced endurance observed in the engineered mice.

Together, the findings reveal that TGF-β1 from a narrowly defined population of M2 macrophages may contribute to obesity-related muscle decline through two distinct but complementary routes. It appears to suppress the cellular signals needed for muscle regeneration while also weakening the hormone-driven pathways that support mitochondrial energy production. Blocking the signal in these macrophages improved muscle size, fiber structure, exercise performance, and metabolic health without reducing obesity itself. The study therefore raises the possibility that future treatments could target the complications of obesity independently of weight loss.

The work remains an experimental finding in mice, and translating it into a human therapy will require substantial further research. TGF-β1 performs many essential functions throughout the body, so broadly blocking the molecule could produce unwanted effects. Any future intervention would likely need to act selectively within the relevant macrophage population or downstream pathways. Nevertheless, the study offers a new framework for treating obesity-related sarcopenia: rather than focusing exclusively on body weight or blood sugar, therapies might also restore the immune, regenerative, and mitochondrial signals that keep skeletal muscle functional. With obesity and aging increasingly occurring together worldwide, targeting this intersection could become an important strategy for preserving strength and independence.

Subject of Research: Animals

Article Title: Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle

Web References: https://doi.org/10.1002/jcsm.70322

References: DOI: 10.1002/jcsm.70322

Image Credits: Distinguished Research Professor Kazuyuki Tobe, University of Toyama

Keywords: obesity-related sarcopenia, skeletal muscle, M2 macrophages, CD206, TGF-β1, muscle regeneration, mitochondria, adiponectin, AMPK, myogenesis

Skeletal muscle injury, a frequent consequence of trauma and degenerative diseases, triggers a complex biological response aimed at restoring muscle function and architecture. Crucial to this reparative process is the timely clearance of damaged fibers and the modulation of inflammation by immune cells, among which macrophages play a central role. Macrophages can adopt diverse phenotypes ranging from pro-inflammatory to tissue reparative, and the mechanisms that dictate this transition remain an intense area of investigation.

Central to this study is the cannabinoid type 2 receptor, a G protein-coupled receptor primarily expressed within immune cells including macrophages, known for its immunomodulatory functions. While CB2R has been implicated in various inflammatory disorders, its role in muscle regeneration and the molecular pathways it influences were poorly understood until now. The researchers employed a combination of genetic models, pharmacological agents, and advanced molecular techniques to dissect the influence of CB2R on macrophage behavior post muscle injury.

The research team discovered that activation of CB2R markedly influences macrophage pyroptosis, a form of programmed cell death characterized by inflammatory cytokine release and cell lysis. This pyroptotic response is orchestrated through the NLRP3 inflammasome, a cytosolic multiprotein complex that detects cellular stress and damage signals, subsequently activating gasdermin D (GSDMD) to execute membrane pore formation. This cascade ultimately facilitates the release of pro-inflammatory mediators essential for orchestrating the regenerative milieu.

Intriguingly, the study demonstrated that muscle injury induces robust activation of the NLRP3 inflammasome within macrophages, which propels GSDMD-mediated pyroptosis. This event aids in clearing cell debris and fostering a local environment conducive to regeneration, but excessive or dysregulated pyroptosis can exacerbate tissue damage. CB2R signaling appears to fine-tune this balance by modulating inflammasome activation and controlling the extent and timing of pyroptotic death.

Using CB2R knockout mice and selective agonists, the investigators observed that loss of CB2R function led to impaired muscle healing characterized by prolonged inflammation, reduced macrophage pyroptosis, and defective clearance of necrotic fibers. Conversely, pharmacological activation of CB2R enhanced NLRP3-GSDMD-driven pyroptosis in macrophages, accelerating muscle regeneration and functional recovery. These findings position CB2R as a molecular switch that regulates the inflammatory cell death pathway during tissue repair.

At a cellular level, the mechanistic underpinnings involve CB2R-mediated signaling pathways that intersect with inflammasome assembly and activation. The researchers identified that CB2R engagement inhibits upstream signals curbing excessive inflammasome activation while promoting timely pyroptosis to maintain inflammatory homeostasis. This nuanced regulation ensures a balanced inflammatory response that mitigates secondary damage and promotes efficient muscle fiber reconstructions.

The implications of these insights extend beyond skeletal muscle biology, opening possibilities for novel therapeutic strategies targeting CB2R in diverse inflammatory and degenerative conditions. The ability to harness cannabinoid receptor pathways to modulate macrophage cell death and orchestrate tissue regeneration heralds a promising avenue for treating muscle dystrophies, acute injuries, and perhaps other organ systems undergoing injury and repair.

This work also sheds light on the broader biological significance of pyroptosis in tissue homeostasis. While traditionally viewed as a defense mechanism against pathogens, pyroptosis in sterile injury conditions like muscle trauma underscores its versatility and importance in physiological processes. By elucidating how CB2R modulates pyroptosis, the study enriches our understanding of how immune cell death pathways can be precisely tuned to serve regenerative ends.

Technologically, the study employed state-of-the-art imaging and molecular assays to visualize inflammasome complex formation, GSDMD cleavage, and macrophage pyroptotic events in vivo. Coupled with transcriptomic analyses, the research delineated the gene expression profiles underpinning CB2R-dependent inflammatory programs, offering a comprehensive molecular blueprint of muscle repair orchestrated by immune receptors.

Beyond molecular intricacies, the findings carry profound clinical relevance. Muscle injuries impose significant burdens on athletes, military personnel, and aging populations. Current therapeutic approaches primarily focus on mitigating inflammation or enhancing myogenic cell proliferation, often with limited success. The identification of CB2R as a regulatory node for innate immune cell death pathways offers a precision-targeted modality to accelerate muscle healing and restore function.

Moreover, this cannabinoid receptor-mediated pathway may present an advantage over traditional anti-inflammatory drugs that broadly suppress immune responses. By selectively modulating pyroptosis, CB2R-targeted therapies could preserve beneficial immune functions while limiting chronic inflammation, thus avoiding the pitfalls of immunosuppression and promoting natural tissue regeneration dynamics.

The study also prompts intriguing questions about the interplay between the endocannabinoid system and immune signaling in other regenerative contexts. Could similar CB2R-dependent mechanisms operate in cardiac tissue repair, neural regeneration, or hepatic injury? The possibility that cannabinoid receptors serve as universal modulators of inflammasome-driven cell death may pave the way for broad-spectrum regenerative medicine interventions.

Additionally, the research revives interest in the therapeutic potential of cannabinoids beyond their psychoactive properties. By delineating discrete receptor-specific roles in inflammation and repair, this work clarifies how non-psychoactive cannabinoid receptor agonists might be harnessed to treat inflammatory diseases without undesirable central nervous system effects, thus expanding their clinical utility.

In conclusion, this compelling study from Li, Yuan, Mu, and colleagues unveils a sophisticated regulatory axis where CB2R governs skeletal muscle regeneration through the modulation of NLRP3-GSDMD-mediated macrophage pyroptosis. This discovery not only advances fundamental understanding of muscle biology but also lays the foundation for innovative therapies targeting immune receptor pathways to enhance tissue repair and recovery. As the scientific community continues to unravel the complexities of immune-regulated regeneration, CB2R stands out as a beacon of therapeutic promise, illuminating new paths toward healing and restoration.

Subject of Research: Cannabinoid type 2 receptor regulation of macrophage pyroptosis in skeletal muscle regeneration

Article Title: Cannabinoid type 2 receptor regulates skeletal muscle regeneration by NLRP3-GSDMD mediated macrophage pyroptosis after injury

Article References:
Li, X., Yuan, H., Mu, S. et al. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03077-z

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-026-03077.z