AMP-activated kinase α2 deficiency protects mice from denervation-induced skeletal muscle atrophy

Guo, Yuting; Ji, Meng; Yi, Tang; Wang, Ting; Wei, Bin; Feng, Run; Gong, Bing; Wang, Huiwen; Ji, Guangju; Lu, Zhigang

doi:10.1016/j.abb.2016.04.015

Cited by 26 publications

(33 citation statements)

References 27 publications

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“…The initial reduction in AMPK activation during the onset of the atrophy program is in agreement with previous studies since inhibition of AMPK has been reported to prevent increased atrogene expression (57,69). Indeed, MuRF1 and MAFbx expression levels were not elevated until 72 hours after denervation, which occurred coincident with a return of AMPK activation status to basal levels.…”

Section: Discussionsupporting

confidence: 79%

“…Several studies have reported increased p38 activity in response to immobilization, hind limb suspension and denervation (53,54,55,56,57,62,66,67,69). In support of the notion that elevation of p38 activity promotes protein degradation, numerous papers have showed that induction of MuRF1 can be blocked by p38 inhibitors and that constitutive activation of p38 induces MuRF1 gene expression in vivo and in vitro (57,63,65).…”

Section: Molecular Mechanisms Of Skeletal Muscle Atrophymentioning

confidence: 92%

“…PGC-1α, AMPK, and p38 expression and/or activity are affected during skeletal muscle atrophy (37,57,58,59,60). Moreover, these powerful phenotype-bending molecules also participate in mediating disuse-induced remodelling (61,62,63,64,65).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, downstream events are currently unclear with respect to p38. Several studies have found that activation of p38 induces muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) (57,60,61,63,64,65,69) expression, while others have shown the opposite outcome (70,71). In response to disuse, the inhibitory effect of PGC-1α and AKT on forkhead box O3a (FOXO3a) is attenuated (43,94), while augmented AMPK activation leads to increased FOXO3a transcriptional activity (76,80).…”

Section: Molecular Mechanisms Of Skeletal Muscle Atrophymentioning

confidence: 99%

“…Transgenic PGC-1α overexpression can impede muscle wasting (42,43,49 Under conditions of chronic muscle disuse, p38 mitogen-activated protein kinase (p38) and AMP-activated protein kinase (AMPK) are activated (53,54,55,56,57,62,66,67,82). However, interventions of this nature reduce peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression (37,43).…”

Section: Molecular Mechanisms Of Skeletal Muscle Atrophymentioning

confidence: 99%

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Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Stouth

Manta

Ljubicic

2018

American Journal of Physiology-Cell Physiology

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Lay AbstractSkeletal muscle is a plastic tissue that is capable of adapting to various physiological demands. Previous work suggests that protein arginine methyltransferases (PRMTs) are important players in the regulation of skeletal muscle remodelling. However, their role in disuse-induced muscle plasticity is unknown. Therefore, the purpose of this study was to investigate the role of PRMTs within the context of early, upstream signaling pathways that mediate disuse-evoked muscle remodelling. We found differential responses of the PRMTs to muscle denervation, suggesting a unique sensitivity to, or regulation by, potential upstream signaling pathways. AMP-activated protein kinase (AMPK) was among the molecules that experienced a rapid change in activity following disuse. These alterations in AMPK predicted many of the modifications in PRMT biology during inactivity, suggesting that PRMTs factor into the molecular mechanisms that precede neurogenic muscle atrophy. This study expands our understanding of the role of PRMTs in regulating skeletal muscle plasticity.

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Section: Discussionsupporting

confidence: 79%

Section: Molecular Mechanisms Of Skeletal Muscle Atrophymentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Molecular Mechanisms Of Skeletal Muscle Atrophymentioning

confidence: 99%

Section: Molecular Mechanisms Of Skeletal Muscle Atrophymentioning

confidence: 99%

See 3 more Smart Citations

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Stouth

Manta

Ljubicic

2018

American Journal of Physiology-Cell Physiology

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Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

Gorski

Mathes

Krützfeldt

2018

J cachexia sarcopenia muscle

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BackgroundIntramuscular fatty infiltration is generally associated with the accumulation of white adipocytes in skeletal muscle and unfavourable metabolic outcomes. It is, however, still unclear whether intramuscular adipocytes could also acquire a brown‐like phenotype. Here, we detected intramuscular expression of brown adipocyte markers during fatty infiltration in an obesity‐resistant mouse strain and extensively compared the potential of two different stem cell populations residing in skeletal muscle to differentiate into brown‐like adipocytes.MethodsFatty infiltration was induced using intramuscular glycerol or cardiotoxin injection in the tibialis anterior muscles of young or aged 129S6/SvEvTac (Sv/129) mice or interleukin‐6 (IL‐6) knockout mice, and the expression of general and brown adipocyte markers was assessed after 4 weeks. Fibro/adipogenic progenitors (FAPs) and myogenic progenitors were prospectively isolated using fluorescence‐activated cell sorting from skeletal muscle of male and female C57Bl6/6J and Sv/129 mice, and monoclonal and polyclonal cultures were treated with brown adipogenic medium. Additionally, FAPs were differentiated with medium supplemented or not with triiodothyronine.ResultsAlthough skeletal muscle expression of uncoupling protein 1 (Ucp1) was barely detectable in uninjected tibialis anterior muscle, it was drastically induced following intramuscular adipogenesis in Sv/129 mice and further increased in response to beta 3‐adrenergic stimulation. Intramuscular Ucp1 expression did not depend on IL‐6 and was preserved in aged skeletal muscle. Myogenic progenitors did not form adipocytes neither in polyclonal nor monoclonal cultures. Fibro/adipogenic progenitors, on the other hand, readily differentiated into brown‐like, UCP1+ adipocytes. Uncoupling protein 1 expression in differentiated FAPs was regulated by genetic background, sex, and triiodothyronine treatment independently of adipogenic differentiation levels.ConclusionsIntramuscular adipogenesis is associated with increased Ucp1 expression in skeletal muscle from obesity‐resistant mice. Fibro/adipogenic progenitors provide a likely source for intramuscular adipocytes expressing UCP1 under control of both genetic and hormonal factors. Therefore, FAPs constitute a possible target for therapies aiming at the browning of intramuscular adipose tissue and the metabolic improvement of skeletal muscle affected by fatty infiltration.

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Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a

Kang

Moon

Lee

et al. 2021

J cachexia sarcopenia muscle

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Background Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first-line and most widely prescribed anti-diabetic drug for patients with type 2 diabetes. The molecular mechanism of metformin in muscle is unclear. Methods Myostatin expression was investigated at the protein and transcript levels after metformin administration. To investigate the pathways associated with myostatin signalling, we used real-time polymerase chain reaction, immunoblotting, luciferase assay, chromatin immunoprecipitation assay, co-immunoprecipitation, immunofluorescence, primary culture, and confocal microscopy. Serum analysis, physical performance, and immunohistochemistry were performed using our in vivo model. Results Metformin induced the expression of myostatin, a key molecule that regulates muscle volume and triggers the phosphorylation of AMPK. AMPK alpha2 knockdown in the background of metformin treatment reduced the myostatin expression of C2C12 myotubes (À49.86 ± 12.03%, P < 0.01) and resulted in increased myotube diameter compared with metformin (+46.62 ± 0.88%, P < 0.001). Metformin induced the interaction between AMPK and FoxO3a, a key transcription factor of myostatin. Metformin also altered the histone deacetylase activity in muscle cells (>3.12fold ± 0.13, P < 0.001). The interaction between HDAC6 and FoxO3a induced after metformin treatment. Confocal microscopy revealed that metformin increased the nuclear localization of FoxO3a (>3.3-fold, P < 0.001). Chromatin immunoprecipitation revealed that metformin induced the binding of FoxO3a to the myostatin promoter. The transcript-level expression of myostatin was higher in the gastrocnemius (GC) muscles of metformin-treated wildtype (WT) (+68.9 ± 10.01%, P < 0.001) and db/db mice (+55.84 ± 6.62%, P < 0.001) than that in the GC of controls (n = 4 per group). Average fibre cross-sectional area data also showed that the metformin-treated C57BL/6J (WT) (À31.74 ± 0.75%, P < 0.001) and C57BLKS/J-db/db (À18.11 ± 0.94%, P < 0.001) mice had decreased fibre size of GC compared to the controls. The serum myoglobin level was significantly decreased in metformin-treated WT mice (À66.6 ± 9.03%, P < 0.01). Conclusions Our results demonstrate that metformin treatment impairs muscle function through the regulation of myostatin in skeletal muscle cells via AMPK-FoxO3a-HDAC6 axis. The muscle-wasting effect of metformin is more evident in WT than in db/db mice, indicating that more complicated mechanisms may be involved in metformin-mediated muscular dysfunction.

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AMP-activated kinase α2 deficiency protects mice from denervation-induced skeletal muscle atrophy

Cited by 26 publications

References 27 publications

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a

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