Complement activation alters myocellular sodium homeostasis during polymicrobial sepsis

Area of Science:

• Physiology
• Immunology
• Biochemistry

Background:

• Sepsis can lead to organ dysfunction, including alterations in skeletal muscle function.
• The role of complement activation and its downstream signaling pathways in sepsis-induced muscle dysfunction remains incompletely understood.

Purpose of the Study:

• To investigate the impact of complement activation on sodium homeostasis in fast-twitch skeletal muscles during sepsis.
• To determine the involvement of protein kinase-C (PKC) in complement-mediated alterations of muscle sodium balance.

Main Methods:

• A prospective, randomized, controlled animal study using male Sprague-Dawley rats.
• Sepsis was induced via cecal ligation and puncture (CLP); treatment with soluble complement receptor-1 (sCR1) was administered.
• Isolated fast-twitch muscles were incubated with normal, zymosan-activated, or heat-inactivated rat sera, with or without PKC inhibitors (GF109203X, rottlerin).
• Intracellular sodium ([Na+]i) and potassium ([K+]i) content was measured.

Main Results:

• Polymicrobial sepsis (CLP) significantly increased [Na+]i and the [Na+]i/[K+]i ratio in fast-twitch muscles.
• Administration of sCR1 attenuated these sepsis-induced changes.
• In vitro, zymosan-activated sera increased myocellular [Na+]i and [Na+]i/[K+]i ratios, an effect blocked by PKC inhibitors.

Conclusions:

• Complement activation contributes to altered sodium homeostasis in skeletal muscle during sepsis.
• PKC activation is identified as a key intracellular signaling pathway mediating these complement-induced changes.
• Targeting complement activation or PKC may offer therapeutic strategies for sepsis-related muscle dysfunction.