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

Liu, Jing; Peng, Yunhua; Cui, Zhiwei; Wu, Zhiming; Qian, Airong; Shang, Peng; Qu, Lei; Li, Yinghui; Liu, Jiankang; Long, Jiangang

doi:10.1002/iub.1087

Cited by 43 publications

(58 citation statements)

References 35 publications

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“…4D). This is consistent with the previous findings that p62 mRNA is upregulated in mouse soleus (10) and gastrocnemius muscle (11) following 3-day hindlimb unloading and that p62 protein is increased by 4-wk hindlimb unloading in mouse tibialis anterior and gastrocnemius muscle (40). Accumulation of p62 generally indicates an impairment of autophagy flux (46), but p62 hyperexpression was also observed in cancer cachexia-induced skeletal muscle atrophy despite the autophagy induction (56).…”

Section: Discussionsupporting

confidence: 92%

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

Egawa

Goto

Ohno

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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-AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT (n ϭ 24) and AMPK-DN (n ϭ 24) mice were randomly divided into two groups: an untreated preexperimental control group (n ϭ 12 in each group) and an unloading (n ϭ 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ϳ30% in WT mice by hindlimb unloading and by ϳ20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of B␣, microRNA (miR)-1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system. AMP-activated protein kinase; protein degradation; autophagy; ubiquitin-proteasome; microRNA; heat shock protein SKELETAL MUSCLE IS THE LARGEST TISSUE IN THE BODY, accounting for ϳ40% of the total body mass, and has a crucial role in metabolism as well as locomotion. Skeletal muscle has a high ability to adapt to multiple stimuli. Increased loading, such as resistance training and mechanical stretching, leads to skeletal muscle hypertrophy (18,75). In contrast, aging, poor nutrition, several diseases such as diabetes, cancer, sepsis, and chronic renal failure, and decreased loading, such as inactivity, lead to skeletal muscle atrophy (23,34,39). Skeletal muscle atrophy occurs as a result of changes in protein turnover: decreased protein synthesis, increased protein degradation, or a combination of both (17). The coordination of protein turnover in the atrophic process is regulated by complicated molecular responses, and the molecular mechanism involved in this process in skeletal muscle is not yet completely understood and remains to be elucidated.5=-AMP-activated protein kinase (AMPK) is well established as a metabolic sensor that helps maintain cellular energy homeostasis by modulating glucose, lipid, and protein metabolism (16,26,28). AMPK is a heterotrimeric kinase comprising a catalytic ␣-subunit and two regulatory subunits, the ␤-and ␥-subunits. Two ...

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Section: Discussionsupporting

confidence: 92%

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

Egawa

Goto

Ohno

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…unloading of the musculature results in mitochondrial fragmentation (loss of tubular mitochondrial networks and appearance of swollen isolated mitochondria), loss of mitochondria, reduced mitochondrial oxygen consumption, and decreased mRNA and protein expression levels of components of the mitochondrial OXPHOS chain (23,26,30,33,39). This is in line with our finding that hindlimb suspension resulted in decreased mRNA and protein levels of several mitochondrial OXPHOS complex subunits.…”

Section: E619 Alternative Nf-b Signaling During Recovery Of Muscle Oxsupporting

confidence: 82%

“…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.…”

Section: E619 Alternative Nf-b Signaling During Recovery Of Muscle Oxsupporting

confidence: 80%

“…It has been convincingly demonstrated that physical inactivity or mechanical unloading, as frequently observed in clinical settings in response to immobilization or prolonged bed rest, leads to a coordinated downregulation of muscle oxidative phenotype (OXPHEN: muscle cell-intrinsic features determining the capacity for substrate oxidation) (23,26,30,33,39). Remarkably, the response of muscle OXPHEN, and specifically its molecular regulation, to resumed physical activity after a period of prolonged inactivity has been scarcely described.…”

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confidence: 99%

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

Remels

Pansters

Gosker

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Mitochondrial biogenesis and dynamics are crucial for maintaining normal mitochondrial function [26]. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a critical regulator of mitochondrial biogenesis, can control the expression of mitochondrial DNA (mtDNA)-encoded intramitochondrial proteins by regulating mitochondrial transcription factor A (TFAM) levels [27].…”

Section: Introductionmentioning

confidence: 99%

Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

Huang¹,

Chen²,

Ren³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Skeletal muscle atrophy is an important health issue and can impose tremendous economic burdens on healthcare systems. Glucocorticoids (GCs) are well-known factors that result in muscle atrophy observed in numerous pathological conditions. Therefore, the development of effective and safe therapeutic strategies for GC-induced muscle atrophy has significant clinical implications. Some natural compounds have been shown to effectively prevent muscle atrophy under several wasting conditions. Dihydromyricetin (DM), the most abundant flavonoid in Ampelopsis grossedentata, has a broad range of health benefits, but its effects on muscle atrophy are unclear. The purpose of this study was to evaluate the effects and underlying mechanisms of DM on muscle atrophy induced by the synthetic GC dexamethasone (Dex). Methods: The effects of DM on Dex-induced muscle atrophy were assessed in Sprague-Dawley rats and L6 myotubes. Muscle mass and myofiber cross-sectional areas were analyzed in gastrocnemius muscles. Muscle function was evaluated by a grip strength test. Myosin heavy chain (MHC) content and myotube diameter were measured in myotubes. Mitochondrial morphology was observed by transmission electron microscopy and confocal laser scanning microscopy. Mitochondrial DNA (mtDNA) was quantified by real-time PCR. Mitochondrial respiratory chain complex activities were examined using the MitoProfile Rapid Microplate Assay Kit, and mitochondrial membrane potential was assessed by JC-1 staining. Protein levels of mitochondrial biogenesis and dynamics markers were detected by western blotting. Myotubes were transfected with siRNAs targeting peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and mitofusin-2 (mfn2) to determine the underlying mechanisms. Results: In vivo, DM preserved muscles from weight and average fiber cross-sectional area losses and improved grip strength. In vitro, DM prevented the decrease in MHC content and myotube diameter. Moreover, DM stimulated mitochondrial biogenesis and promoted mitochondrial fusion, rescued the reduced mtDNA content, improved mitochondrial morphology, prevented the collapse in mitochondrial membrane potential and enhanced mitochondrial respiratory chain complex activities; these changes restored mitochondrial function and improved protein metabolism, contributing to the prevention of Dex-induced muscle atrophy. Furthermore, the protective effects of DM on mitochondrial function and muscle atrophy were alleviated by PGC-1α siRNA, TFAM siRNA and mfn2 siRNA transfection in vitro. Conclusion: DM attenuated Dex-induced muscle atrophy by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/TFAM and PGC-1α/mfn2 signaling pathways. Our findings may open new avenues for identifying natural compounds that improve mitochondrial function as promising candidates for the management of muscle atrophy.

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

Cited by 43 publications

References 35 publications

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

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

Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

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