Expression of nuclear-encoded genes involved in mitochondrial biogenesis and dynamics in experimentally denervated muscle

Abstract

The abundance, morphology, and functional properties of mitochondria become altered in response to denervation. To gain insight into the regulation of this process, mitochondrial enzyme activities and gene expression involved in mitochondrial biogenesis and dynamics in mouse gastrocnemius muscle was investigated. Sciatic nerve transactions were performed on mice, and then gastrocnemius muscles were isolated at days 5 and 30 after surgery. Muscle weight was decreased significantly by 15% and 62% at days 5 and 30 after surgery, respectively. The activity of citrate synthase, a marker of oxidative enzyme, was reduced significantly by 31% and 53% at days 5 and 30, respectively. Enzyme histochemical analysis revealed that subsarcolemmal mitochondria were largely lost than intermyofibrillar mitochondria at day 5, and this trend was further progressed at day 30 after surgery. Expression levels of peroxisome proliferator-activated receptor, γ coactivator 1 (PGC-1)α, estrogen-related receptor α (ERRα), and mitofusin 2 were down-regulated throughout the experimental period, whereas those of PGC-1β, PRC, nuclear respiratory factor (NRF)-1, NRF-2, TFAM, and Lon protease were down-regulated at day 30 after surgery. These results suggest that PGC-1α, ERRα, and mitofusin 2 may be important factors in the process of denervation-induced mitochondrial adaptation. In addition, other PGC-1 family of transcriptional coactivators and DNA binding transcription factors may also contribute to mitochondrial adaptation after early response to denervation.

Activation of alternative NF-κB signaling during recovery of disuse-induced loss of muscle oxidative phenotype

“…In addition, we observed that unloading significantly decreased mRNA expression levels of Tfam and ERR-␣, which is in line with data from Wagatsuma et al who reported decreased expression levels of these regulators in soleus muscle of hindlimb-suspended rats (45). Interestingly, decreased expression levels of PGC-1 molecules and ERR-␣ are also observed in other models of disuse-induced loss of muscle OXPHEN such as denervation and spaceflight-induced gravitational unloading, suggesting that disuse of the musculature in broad terms initiates a conserved transcriptional program that leads to a coordinated downregulation of muscle OXPHEN (1,35,46). Although the focus of this study was not to investigate the impact of disuse on muscle OXPHEN and its molecular regulation, we identified that only a subset of the regulators we investigated shows decreased expression levels upon unloading (PGC-1␤, Tfam, and ERR-␣), whereas the mRNA abundance of other regulatory molecules such as NRF-1, NRF-2␣, PPAR-␦, and SIRT-1 remained unaltered.…”

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…In muscle taken within 10 days from children with severe burn injury, downregulated mitochondrial biogenesis has been suggested (723). In experimentally denervated gastrocnemius muscle of rats and mice (a model of disuse), strong reductions in mitochondrial content coincided with a remarkable downregulation of several key players of mitochondrial biogenesis several weeks after the insult (5,750). Several components of the mitochondrial biogenesis pathway appeared downregulated at gene expression level after 24 h of endotoxemia, which was more pronounced in mouse tibialis anterior and soleus muscle than in diaphragm (490).…”

Mitochondrial Lon protease in human disease and aging: Including an etiologic classification of Lon-related diseases and disorders

“…In the experimental model of sciatic nerve transection, Lon protease was down-regulated at day 30 after surgery, which correlated with a decreased number of functional mitochondria [83]. …”