Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle
Authors: Pieter A Leermakers
Ramon C J Langen
Alexander H V Remels
Annemie M W J Schols
Harry R Gosker
Journal: BMC Pulmonary Medicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: Inflammation; Mitochondrial biogenesis; Mitophagy; Skeletal muscle.
Affiliations: Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands., Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands., Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands. .

Abstract:  Background: Both 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. Methods: We 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. Results: Both 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. Conclusions: These 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. 

Retracted: No

PubPeer comments:
 Gurumurthy, Channabasavaiah B., et al.  Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation. Genome biology 20.1 (2019): 1-14. PMID: 31446895. This paper conducted by multiple independent laboratories pointed out a lack of reproducibility of the original research. ,