Mitochondrial adaptations in skeletal muscle to hindlimb unloading

Abstract

To gain insight into the regulation of mitochondrial adaptations to hindlimb unloading (HU), the activity of mitochondrial enzymes and the expression of nuclear-encoded genes which control mitochondrial properties in mouse gastrocnemius muscle were investigated. Biochemical and enzyme histochemical analysis showed that subsarcolemmal mitochondria were lost largely than intermyofibrillar mitochondria after HU. Gene expression analysis revealed disturbed or diminished gene expression patterns. The three main results of this analysis are as follows. First, in contrast to peroxisome proliferator-activated receptor γ coactivator 1 β (PGC-1β) and PGC-1-related coactivator, which were down-regulated by HU, PGC-1α was up-regulated concomitant with decreased expression of its DNA binding transcription factors, PPARα, and estrogen-related receptor α (ERRα). Moreover, there was no alteration in expression of nuclear respiratory factor 1, but its downstream target gene, mitochondrial transcription factor A, was down-regulated. Second, both mitofusin 2 and fission 1, which control mitochondrial morphology, were down-regulated. Third, ATP-dependent Lon protease, which participates in mitochondrial-protein degradation, was also down-regulated. These findings suggest that HU may induce uncoordinated expression of PGC-1 family coactivators and DNA binding transcription factors, resulting in reducing ability of mitochondrial biogenesis. Furthermore, down-regulation of mitochondrial morphology-related genes associated with HU may be also involved in alterations in intracellular mitochondrial distribution.

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

“…Although we did observe some variability in mRNA expression levels of several OXPHEN regulators in response to hindlimb suspension, our finding that hindlimb suspension induced significant decreases in PGC-1␤ mRNA expression levels is in line with previous reports. 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).…”

“…Several studies have investigated the impact of unloading on expression levels of these regulators. Decreased expression levels of PGC-1␣ and PGC-1␤ but also of the PGC-1-related cofactor upon unloading have been consistently reported (23,27,45). Although we did observe some variability in mRNA expression levels of several OXPHEN regulators in response to hindlimb suspension, our finding that hindlimb suspension induced significant decreases in PGC-1␤ mRNA expression levels is in line with previous reports.…”

“…Because Tfam and NRF-1 protein did not decrease upon unloading, other factors involved in the regulation of muscle OXPHEN must be responsible for loss of muscle OXPHEN upon unloading. In general, the unloading-induced alterations in mRNA expression levels of constituents of PGC-1 signaling are in line with studies from Cassano et al and a report from Wagatsuma et al that showed that, although ERR-␣ and Tfam mRNA levels were downregulated upon unloading, NRF-1 mRNA levels were unaltered in rat soleus muscle and mouse gastrocnemius muscle, respectively, after 14 or 7 days of unloading (12,45). Qi et al, on the other hand, demonstrated that NRF-1 mRNA levels were potently decreased in rat skeletal muscle after 3 wk of hindlimb suspension (31).…”

Depressed mitochondrial biogenesis and dynamic remodeling in mouse tibialis anterior and gastrocnemius induced by 4‐week hindlimb unloading

“…Mfn1 and Mfn2 are the two key proteins on the outer membrane of mitochondria responsible for its fusion (34), while mitochondrial fission is mediated by Drp1 (15). Consisting with an earlier report (35), our results showed that the mitochondrial molecules involved in fusion and fission were repressed following unloading. These alterations suggested that mitochondria are less dynamic in disuse muscles.…”

Skeletal muscle mass and composition during mammalian hibernation

“…For example, hindlimb suspension (Thomason and Booth, 1990), bed rest (Widrick et al, 1997) and denervation (Hornberger et al, 2001) are all accepted models for investigating decreased activity and disuse atrophy. Commonalities amongst these models are a decrease in muscle mass (Musacchia et al, 1983;Thomason et al, 1987), protein concentration (Bajotto and Shimomura, 2006;Larsson et al, 1996) and fiber size (Pellegrino and Franzini, 1963;Rittweger et al, 2005;Wagatsuma et al, 2011). Most studies also show a conversion from slow to fast fiber types (Boonyarom and Inui, 2006) and a decline in muscle strength (Adams et al, 2003;Larsson et al, 1996;Thomason and Booth, 1990).…”