Abstract
BackgroundBoth mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation.MethodsWe investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle.ResultsBoth in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found.ConclusionsThese data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.
Highlights
Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature
Receptor-mediated mitophagy is regulated through activation of mitophagy-receptors like BCL2/adenovirus E1B 19 kDa protein interacting protein 3 (BNIP3), BNIP3 like (BNIP3L), or FUN14 domain containing 1 (FUNDC1), while ubiquitin-mediated mitophagy is activated by a loss of mitochondrial membrane potential and is initiated by the recruitment/activation of proteins like PTEN induced putative kinase 1 (PINK1) and Parkin (PARK2)
To determine the impact of a single bolus of instillation of μg lipopolysaccharide (IT-LPS) on key processes regulating mitochondrial content, we first assessed mRNA transcript levels and protein abundance of key proteins involved in mitophagy in gastrocnemius muscle at several time-points after IT-LPS instillation
Summary
A selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature Abnormalities in these processes could contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Receptor-mediated mitophagy is regulated through activation of mitophagy-receptors like BCL2/adenovirus E1B 19 kDa protein interacting protein 3 (BNIP3), BNIP3 like (BNIP3L), or FUN14 domain containing 1 (FUNDC1), while ubiquitin-mediated mitophagy is activated by a loss of mitochondrial membrane potential and is initiated by the recruitment/activation of proteins like PTEN induced putative kinase 1 (PINK1) and Parkin (PARK2) Both these pathways eventually result in the recruitment of general autophagy proteins to facilitate autophagosomal membrane formation around the mitochondrion and predestines the organelle for degradation [8,9,10,11,12,13]. Mitochondrial biogenesis, on the other hand, is essentially controlled by the peroxisome proliferative activated receptor (PPAR), gamma, coactivator 1 (PPARGC1) signalling network, which is comprised of many different transcription factors regulating the coordinated transcription of nuclear- and mitochondrial-DNA encoded metabolic genes [14]
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