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Updated: Nov 10, 2025
Author Spotlight: Advanced Integrated Model for Sepsis-Induced Myopathy and Single-Cell Metabolic Analysis
Published on: June 14, 2024
Skeletal muscle fibers play a functional role in host defense during sepsis in mice
Orlando Laitano1, Gerard P Robinson1, Kevin O Murray1
1Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Rd, Gainesville, FL, 32611, USA.
Abstract:
Skeletal muscles secrete a wide variety of immunologically active cytokines, but the functional significance of this response to in vivo innate immunity is not understood. We addressed this by knocking out the toll receptor adapter protein, Myd88, only in skeletal muscle fibers (skmMyd88KO), and followed male and female mice at 6 and 12 h after peritoneal injection of cecal slurry (CS), a model of polymicrobial sepsis. Because of a previously identified increase in mortality to CS injection, males received ~ 30% lower dose. At 12 h, skmMyd88KO caused significant reductions in a wide variety of pro- and anti-inflammatory plasma cytokines, e.g. TNFα, IL-1β and IL-10, compared to strain-matched controls in both males and females. Similar reductions were observed at 6 h in females. SkmMyd88KO led to ~ 40-50% elevations in peritoneal neutrophils at 6 and 12 h post CS in females. At 12 h post CS, skmMyd88KO increased peritoneal monocytes/macrophages and decreased %eosinophils and %basophils in females. SkmMyd88KO also led to significantly higher rates of mortality in female mice but not in males. In conclusion, the results suggest that skeletal muscle Myd88-dependent signal transduction can play functionally important role in normal whole body, innate immune inflammatory responses to peritoneal sepsis.
Insights
Skeletal muscle Myd88 signaling influences innate immunity during sepsis. Muscle-specific knockout mice showed altered cytokine profiles and immune cell responses, impacting sepsis survival, particularly in females.
Area of Science:
- Immunology
- Skeletal Muscle Physiology
- Innate Immunity
Background:
- Skeletal muscles produce immunologically active cytokines.
- The role of muscle-derived cytokines in innate immunity is not fully understood.
- Myeloid differentiation primary response 88 (Myd88) is a key adapter protein in innate immune signaling.
Purpose of the Study:
- To investigate the functional significance of skeletal muscle Myd88 signaling in innate immunity during polymicrobial sepsis.
- To determine the impact of muscle-specific Myd88 knockout on immune responses and survival.
Main Methods:
- Generated skeletal muscle-specific Myd88 knockout mice (skmMyd88KO).
- Administered cecal slurry (CS) to induce polymicrobial sepsis.
- Analyzed plasma cytokine levels and peritoneal immune cell populations at 6 and 12 hours post-CS.
Main Results:
- skmMyd88KO mice exhibited reduced pro- and anti-inflammatory plasma cytokines (TNFα, IL-1β, IL-10) post-CS.
- Females with skmMyd88KO showed increased peritoneal neutrophils, monocytes/macrophages, and altered eosinophil/basophil percentages.
- skmMyd88KO led to significantly higher mortality rates in female mice but not males.
Conclusions:
- Skeletal muscle Myd88-dependent signaling plays a crucial role in the systemic innate immune response to sepsis.
- Muscle Myd88 signaling impacts cytokine production and immune cell recruitment during sepsis.
- Disruption of muscle Myd88 signaling has sex-specific effects on sepsis outcomes.
