Potential for a Novel Therapeutic Drug to Suppress Sepsis-Associated Muscle Wasting

A research group led by Assistant Professor Ikumi Yoshihara and Professor Yutaka Kondo at Juntendo University's Graduate School of Medicine, Department of Emergency and Disaster Medicine, has elucidated the progression mechanism of sepsis-associated muscle atrophy and proposed a new treatment approach. Until now, the causes of sepsis-associated muscle atrophy were considered multifactorial, and it was unclear which factors were most significant. Therefore, this research group applied studies on artificial hibernation and discovered that muscle atrophy is primarily driven by hyperinflammatory cytokineemia, with interleukin-1β (a representative inflammatory cytokine) playing a key role in disease onset. Furthermore, they confirmed that administering adenosine 5’-monophosphate (AMP) suppresses this muscle atrophy. This result indicates the potential for a novel pharmacological therapy using AMP for sepsis-induced muscle wasting, a condition for which no drug-based treatment existed beyond musculoskeletal rehabilitation.

The paper was published online in the Journal of Intensive Care on July 4, 2026.

Key Findings of This Research

- Discovered that interleukin-1β plays a crucial role in the progression of sepsis-associated muscle atrophy

- Confirmed that AMP, which has artificial hibernation properties, suppresses sepsis-associated muscle atrophy

- Demonstrated the potential for developing a new pharmacological treatment for sepsis-associated muscle atrophy, a condition previously lacking drug-based therapies

Background

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection. While recent advances in treatment have improved survival rates, sepsis-associated muscle atrophy has emerged as a critical factor influencing patient prognosis. This muscle wasting significantly impacts patients’ physical recovery and social reintegration. Multiple mechanisms, including inflammatory cytokines, oxidative stress, and protein metabolism abnormalities, are thought to contribute to its onset. However, the key factors driving sepsis-associated muscle atrophy remained unclear. Meanwhile, AMP has long been known to induce artificial hibernation and may possess organ-protective effects. Therefore, this study investigated the molecular mechanisms of sepsis-associated muscle atrophy and the suppressive effects of AMP, focusing on cytokine expression, AMPK activation, and comprehensive gene expression analysis.

Study Content

In cellular experiments, the research team used C2C12 myotubes and RAW264.7 macrophage cells to evaluate the effects of AMP. In animal experiments, a sepsis model was created in male C57BL/6 mice via cecal ligation and puncture, followed by intraperitoneal administration of AMP to assess its effects. The study included grip strength measurements, blood and muscle tissue analyses, Western blotting, RNA sequencing, ELISA, flow cytometry, real-time PCR, immunohistochemical staining, and histological evaluations. Additionally, analyses were conducted using plasma from human sepsis patients. The results showed that in plasma from human sepsis patients, inflammatory cytokines were elevated in cases with muscle atrophy. In both cellular and animal experiments, AMP suppressed the production of inflammatory cytokines associated with sepsis and restored muscle mass and strength in septic animals through regulation of AMPK signaling and inhibition of mTORC1 activation. Moreover, AMP inhibited endotoxin-induced interleukin-1β production in RAW264.7 macrophage cells and reduced endotoxin- or interleukin-1β-induced muscle atrophy in C2C12 myotubes.

These results clarify that sepsis-associated muscle atrophy is driven by high levels of interleukin-1β in the bloodstream. Furthermore, AMP administration activates AMPK in muscle cells and suppresses Fbx32 expression, indicating a potential mechanism for inhibiting sepsis-associated muscle atrophy (Figure 1).

Future Outlook

This research group has now elucidated the pathogenesis of sepsis-associated muscle atrophy—a condition previously lacking both treatment options and a clear understanding of its mechanism. Moreover, this is the first study to demonstrate that AMP can suppress this type of muscle wasting. If this treatment approach is clinically applied, it could potentially relieve millions of patients worldwide who suffer from long-term complications even after recovering from sepsis.

Figure 1: Mechanism of sepsis-associated muscle atrophy and the action of AMP revealed in this study

In sepsis, muscle atrophy is triggered by interleukin-1β released from inflammatory cells such as macrophages. AMP acts on muscle cells to activate AMPK and simultaneously acts on inflammatory cells to suppress the release of interleukin-1β. As a result, Fbx32 expression in muscle cells is suppressed, preventing sepsis-associated muscle atrophy.

Glossary

Sepsis: A severe, life-threatening condition in which the body's response to infection becomes excessive and uncontrolled, leading to systemic organ failure. It is one of the leading causes of death worldwide, with approximately 11 million deaths annually.

Sepsis-associated muscle atrophy: A condition characterized by loss of skeletal muscle mass and strength due to systemic inflammation and metabolic disturbances during sepsis, significantly affecting physical recovery and long-term outcomes.

Inflammatory cytokines: Biologically active substances produced by immune cells that promote and regulate inflammatory responses, playing a crucial role in infection defense. However, excessive production can lead to tissue and organ damage.

AMP: A type of adenine nucleotide involved in energy metabolism within the body, playing a vital role in cellular energy homeostasis and metabolic regulation.

AMPK: Short for AMP-activated protein kinase, a key metabolic regulator that senses cellular energy status and becomes activated under energy-deficient conditions. It plays an essential role in maintaining physiological homeostasis.

Original Research Paper

This study was published online in the Journal of Intensive Care on July 4, 2026.

Title: Adenosine 5'-monophosphate prevents sepsis-associated muscle wasting by activating AMPK and suppressing IL-1β inflammatory cytokines

Title (Japanese translation): Adenosine 5'-monophosphate prevents sepsis-associated muscle wasting by activating AMPK and suppressing IL-1β inflammatory cytokines

Authors: Ikumi Yoshihara1, Narumi Yoshihara1, Kei Hanafusa2,3, Koichiro Sueyoshi1, Yuko Ono1, Nao Umei1, Shin Watanabe1, Ken Okamoto1, Hiroshi Tanaka1, Yutaka Kondo1*

Authors (in Japanese): Ikumi Yoshihara1), Narumi Yoshihara1), Kei Hanafusa2)3), Koichiro Sueyoshi1), Yuko Ono1), Nao Umei1), Shin Watanabe1), Ken Okamoto1), Hiroshi Tanaka1), Yutaka Kondo1)

Affiliations: 1) Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University; 2) Institute of Environmental Medicine, Juntendo University; 3) Faculty of Pharmaceutical Sciences, Juntendo University

DOI: https://doi.org/10.1186/s40560-026-00901-7

This study was supported by JSPS KAKENHI Grants JP24KJ1980 and JP25K12250.