PGC1‐α over‐expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice

Abstract

Key pointsr Oxidative stress is widely considered a major cause of muscle loss not only in disuse but also in most chronic diseases, triggering carbonylation of proteins and activation of catabolic pathways involved in their degradation.r Here we show that administration of an antioxidant prevents redox imbalance, but does not prevent activation of catabolic pathways and muscle atrophy.r We indicate that alterations of oxidative metabolism, occurring in slow soleus muscle, are not just a consequence of disuse, but a major cause of activation of catabolic pathways and loss of mass. r This conclusion is confirmed by the observation that muscle-specific overexpression of PGC-1α, a master regulator of mitochondrial biogenesis, prevents activation of catabolic systems and disuse muscle atrophy.r These findings contribute to a better mechanistic understanding of disuse muscle loss.Abstract Prolonged skeletal muscle inactivity causes muscle fibre atrophy. Redox imbalance has been considered one of the major triggers of skeletal muscle disuse atrophy, but whether redox imbalance is actually the major cause or simply a consequence of muscle disuse remains of debate. Here we hypothesized that a metabolic stress mediated by PGC-1α down-regulation plays a major role in disuse atrophy. First we studied the adaptations of soleus to mice hindlimb unloading (HU) in the early phase of disuse (3 and 7 days of HU) with and without antioxidant treatment (trolox). HU caused a reduction in cross-sectional area, redox status alteration (NRF2, SOD1 and catalase up-regulation), and induction of the ubiquitin proteasome system (MuRF-1 and atrogin-1 mRNA up-regulation) and autophagy (Beclin1 and p62 mRNA up-regulation). Trolox completely prevented the induction of NRF2, SOD1 and catalase mRNAs, but not atrophy or induction of catabolic systems in unloaded muscles, suggesting that oxidative stress is not a major cause of disuse atrophy. HU mice showed a marked alteration of oxidative metabolism. PGC-1α and mitochondrial complexes were down-regulated and DRP1 was up-regulated. To define the link between mitochondrial dysfunction and disuse muscle atrophy we unloaded mice overexpressing PGC-1α. Transgenic PGC-1α animals did not show metabolic alteration during unloading, preserving muscle size through the reduction of autophagy and proteasome degradation. Our results indicate that mitochondrial dysfunction plays a major role in disuse Abbreviations CSA, cross-sectional area; CuZnSOD1, superoxide dismutase1; DHE, dihydroethidium; DNP, dinitrophenylhydrazone; DRPI, dynamin-related protein 1; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; HU, hindlimb unloading; MHC, myosin heavy chain; MuRF-1, muscle-specific ring finger protein-1; NRF2, nuclear factor erythroid derived 2 like 2 (Nfe2l2); OI, oxidative index; PGC-1α, peroxisome proliferative activated receptor-γ coactivator 1α; ROS, reactive oxygen species.

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

“…It was previously demonstrated that maximal expression of both MuRF1 and MAFbx is reached after 3 days of unloading (Cannavino et al. 2014; Shenkman et al. 2015).…”

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…The few studies conducted in human observed that carbonylated protein levels did not change in the vastus lateralis after 8 and 14 days of bed rest [66,67], but became higher after 35 days [66]. In rodents, some studies reported an increase of carbonylated proteins in the soleus during the first week of hindlimb unloading [57,[68][69][70], whereas other reports did not observed such effect after 3, 7 and 14 days of hindlimb unloading [53,60,62]. A more restricted number of studies focused on the effects of immobilization on α,β-unsaturated aldehydes (e.g., 4-HNE, MDA), markers of lipid peroxidation.…”

“…On one hand, the ratio GSH/GSSG decreases in skeletal muscle during hindlimb unloading [59][60][61]. On the other hand, immobilization causes, in skeletal muscle, an increase of SOD1 and catalase protein content and activities [53,57,59,[61][62][63][64], whereas SOD2 protein content and activity do not change [61,[63][64][65].…”

“…Indeed, numerous studies demonstrated that a reduction in muscle protein fractional synthesis rate (FSR) occurs in the first days of immobilization [53,75,76]. This rapid reduction of protein synthesis persists for several weeks since a decrease of muscle FSR has been also reported in human skeletal muscle after 14 and 28 days of bed rest [77,78].…”

“…Data from animals, and more recently from humans, indicate that immobilization increases O 2 -and H 2 O 2 emissions in skeletal muscle [52][53][54][55][56]. Mitochondria contributes to muscle ROS production during immobilization [52, [54][55][56], but other studies highlight that XO plays also an important role [57,58].…”