Abstract
Objective: Systemic inflammation has been implicated in skeletal muscle mitochondrial impairment of patients with COPD. Both mitophagy, a selective mitochondrial clearance mechanism, and mitochondrial biogenesis are required for mitochondrial homeostasis. We hypothesized that inflammation-induced loss of muscle mitochondrial capacity is associated with decreased mitochondrial biogenesis and increased mitophagy.
Methods: Mice were subjected to a single intratracheal instillation of lipopolysaccharide (IT-LPS) or NaCl. On several time-points post IT-LPS, muscle (m. gastrocnemius) mitochondrial capacity was assessed by oxidative phosphorylation (OXPHOS) protein levels and citrate synthase (CS) activity. Mitochondrial biogenesis key-regulator protein/mRNA, mitophagy-related protein/mRNA, and autophagy-related mRNA levels were assessed.
Results: Post IT-LPS, OXPHOS protein levels and CS activity were decreased (72h). Moreover, expression levels of key mitochondrial biogenesis regulators were decreased for multiple mRNA targets (48-72h), and PGC-1α (72h) protein, but increased for NRF-1 (72-96h) and TFAM (96h) protein. Autophagy/mitophagy-related mRNA expression was increased for BNIP3L, LC3B, GABARAPL1 (24-48h), and P62 (24-72h). Mitophagy-related protein levels were increased for BNIP3L (24-120h), Parkin (48-120h), or decreased for FUNDC1 (72h).
Conclusion: Systemic inflammation-induced loss of muscle mitochondrial capacity is associated with reduced mitochondrial biogenesis and increased mitophagy-associated protein expression profiles in vivo. Recovery of mitochondrial capacity is associated with mitochondrial biogenesis as well as prolonged mitophagy signaling.
- Copyright ©the authors 2016
