Protein kinase C-λ drives third-degree burn-induced muscle wasting via STAT3-dependent catabolic pathways

Severe burn injury triggers profound skeletal muscle atrophy through incompletely understood molecular mechanisms. This study investigated the role of protein kinase C (PKC) isoforms in burn-induced muscle wasting and evaluated potential therapeutic targets.

We examined PKC isoform expression in skeletal muscle biopsies from burn patients with second-degree (n = 5) and third-degree burns (n = 5) at 7 days post-injury. Mouse burn models were established to investigate PKC signaling at 14 days post-injury. Muscle-specific PKC-lambda (PKC-λ) knockout mice and pharmacological inhibition with [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1) were employed. C2C12 myotubes were used for mechanistic studies with signal transducer and activator of transcription 3 (STAT3) overexpression experiments.

Among six PKC isoforms examined, only PKC-λ was selectively upregulated in third-degree versus second-degree burns in both humans and mice. Third-degree burns caused 39.5% muscle mass loss and 57.3% grip strength reduction, accompanied by PKC-λ activation and downstream STAT3-CCAAT/enhancer-binding protein delta (C/EBPδ)/myostatin catabolic signaling. Muscle-specific PKC-λ knockout mice showed significant protection against burn-induced muscle atrophy. In vitro studies demonstrated that PKC-λ regulates muscle catabolism through STAT3 activation, as STAT3 overexpression reversed protective effects of PKC-λ inhibition. Pharmacological PKC-λ inhibition with ICA-1 restored muscle mass to 85.5% and grip strength to 73.6% of control levels while suppressing the PKC-λ/STAT3-C/EBPδ catabolic cascade.

PKC-λ serves as a critical upstream mediator linking severe burn injury to skeletal muscle atrophy through STAT3-C/EBPδ catabolic signaling. These findings establish PKC-λ as a promising therapeutic target for preventing burn-induced muscle wasting.