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Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation.

ABSTRACT: INTRODUCTION:Physical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading. METHODS:We analyzed a comprehensive set of molecular markers involved in mitochondrial-autophagy, -biogenesis, -dynamics, and -content, in the gastrocnemius muscle of C57BL/6J mice subjected to 0- and 3-days hind limb suspension, and in biopsies from human vastus lateralis muscle obtained before and after 7?days of one-leg immobilization. RESULTS:In both mice and men, short-term skeletal muscle unloading results in molecular marker patterns indicative of increased receptor-mediated mitophagy and decreased mitochondrial biogenesis regulation, before apparent loss of mitochondrial content. DISCUSSION:These results emphasize the early-onset of skeletal muscle disuse-induced mitochondrial remodeling.

SUBMITTER: Leermakers PA

PROVIDER: S-EPMC6900132 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation.

Leermakers Pieter A PA Kneppers Anita E M AEM Schols Annemie M W J AMWJ Kelders Marco C J M MCJM de Theije Chiel C CC Verdijk Lex B LB van Loon Luc J C LJC Langen Ramon C J RCJ Gosker Harry R HR

Muscle & nerve 20191023 6

<h4>Introduction</h4>Physical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading.<h4>Meth ...[more]

PMID: 31495926

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Project description: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.

Dataset Information

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation.

Publications

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation.

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