High CO2Levels Cause Skeletal Muscle Atrophy via AMP-activated Kinase (AMPK), FoxO3a Protein, and Muscle-specific Ring Finger Protein 1 (MuRF1)

A good quality of life requires maintaining adequate skeletal muscle mass and strength, but therapeutic agents are lacking for this. We developed a bioassay-guided fractionation approach to identify molecules with hypertrophy-promoting effect in human skeletal muscle cells. We found that extracts from rosemary leaves induce muscle cell hypertrophy. By bioassay-guided purification we identified the phenolic diterpene carnosol as the compound responsible for the hypertrophy-promoting activity of rosemary leaf extracts. We then evaluated the impact of carnosol on the different signaling pathways involved in the control of muscle cell size. We found that activation of the NRF2 signaling pathway by carnosol is not sufficient to mediate its hypertrophy-promoting effect. Moreover, carnosol inhibits the expression of the ubiquitin ligase E3 Muscle RING Finger protein-1 that plays an important role in muscle remodeling, but has no effect on the protein synthesis pathway controlled by the protein kinase B/mechanistic target of rapamycin pathway. By measuring the chymotrypsin-like activity of the proteasome, we found that proteasome activity was significantly decreased by carnosol and Muscle RING Finger 1 inactivation. These results strongly suggest that carnosol can induce skeletal muscle hypertrophy by repressing the ubiquitin-proteasome system-dependent protein degradation pathway through inhibition of the E3 ubiquitin ligase Muscle RING Finger protein-1.

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Identification and characterization of Fbxl22, a novel skeletal muscle atrophy-promoting E3 ubiquitin ligase

AJP Cell Physiology ◽

10.1152/ajpcell.00253.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. C700-C719 ◽

Cited By ~ 1

Author(s):

David C. Hughes ◽

Leslie M. Baehr ◽

Julia R. Driscoll ◽

Sarah A. Lynch ◽

David S. Waddell ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Splice Variant ◽

Splice Variants ◽

Ring Finger ◽

Ubiquitin Ligases ◽

Skeletal Muscle Atrophy ◽

E3 Ubiquitin Ligases ◽

Muscle Mass Loss

Muscle-specific E3 ubiquitin ligases have been identified in muscle atrophy-inducing conditions. The purpose of the current study was to explore the functional role of F-box and leucine-rich protein 22 (Fbxl22), and a newly identified splice variant (Fbxl22–193), in skeletal muscle homeostasis and neurogenic muscle atrophy. In mouse C2C12 muscle cells, promoter fragments of the Fbxl22 gene were cloned and fused with the secreted alkaline phosphatase reporter gene to assess the transcriptional regulation of Fbxl22. The tibialis anterior muscles of male C57/BL6 mice (12–16 wk old) were electroporated with expression plasmids containing the cDNA of two Fbxl22 splice variants and tissues collected after 7, 14, and 28 days. Gastrocnemius muscles of wild-type and muscle-specific RING finger 1 knockout (MuRF1 KO) mice were electroporated with an Fbxl22 RNAi or empty plasmid and denervated 3 days posttransfection, and tissues were collected 7 days postdenervation. The full-length gene and novel splice variant are transcriptionally induced early (after 3 days) during neurogenic muscle atrophy. In vivo overexpression of Fbxl22 isoforms in mouse skeletal muscle leads to evidence of myopathy/atrophy, suggesting that both are involved in the process of neurogenic muscle atrophy. Knockdown of Fbxl22 in the muscles of MuRF1 KO mice resulted in significant additive muscle sparing 7 days after denervation. Targeting two E3 ubiquitin ligases appears to have a strong additive effect on protecting muscle mass loss with denervation, and these findings have important implications in the development of therapeutic strategies to treat muscle atrophy.

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miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export

AJP Cell Physiology ◽

10.1152/ajpcell.00266.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. C551-C558 ◽

Cited By ~ 74

Author(s):

Matthew B. Hudson ◽

Myra E. Woodworth-Hobbs ◽

Bin Zheng ◽

Jill A. Rahnert ◽

Mitsi A. Blount ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Ring Finger ◽

Skeletal Muscle Atrophy ◽

C2c12 Myotubes ◽

Activated T Cells ◽

Streptozotocin Induced Diabetes ◽

The Media ◽

The Relationship ◽

Deficient Mice

Skeletal muscle atrophy is prevalent in chronic diseases, and microRNAs (miRs) may play a key role in the wasting process. miR-23a was previously shown to inhibit the expression of atrogin-1 and muscle RING-finger protein-1 (MuRF1) in muscle. It also was reported to be regulated by cytoplasmic nuclear factor of activated T cells 3 (NFATc3) in cardiomyocytes. The objective of this study was to determine if miR-23a is regulated during muscle atrophy and to evaluate the relationship between calcineurin (Cn)/NFAT signaling and miR-23a expression in skeletal muscle cells during atrophy. miR-23a was decreased in the gastrocnemius of rats with acute streptozotocin-induced diabetes, a condition known to increase atrogin-1 and MuRF1 expression and cause atrophy. Treatment of C2C12 myotubes with dexamethasone (Dex) for 48 h also reduced miR-23a as well as RCAN1.4 mRNA, which is transcriptionally regulated by NFAT. NFATc3 nuclear localization and the amount of miR-23a decreased rapidly within 1 h of Dex administration, suggesting a link between Cn signaling and miR-23a. The level of miR-23a was lower in primary myotubes from mice lacking the α- or β-isoform of the CnA catalytic subunit than wild-type mice. Dex did not further suppress miR-23a in myotubes from Cn-deficient mice. Overexpression of CnAβ in C2C12 myotubes prevented Dex-induced suppression of miR-23a. Finally, miR-23a was present in exosomes isolated from the media of C2C12 myotubes, and Dex increased its exosomal abundance. Dex did not alter the number of exosomes released into the media. We conclude that atrophy-inducing conditions downregulate miR-23a in muscle by mechanisms involving attenuated Cn/NFAT signaling and selective packaging into exosomes.

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Hydrogen sulphide ameliorating skeletal muscle atrophy in db/db mice via Muscle RING finger 1 S‐sulfhydration

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.15587 ◽

2020 ◽

Vol 24 (16) ◽

pp. 9362-9377 ◽

Cited By ~ 1

Author(s):

Fangping Lu ◽

Baoling Lu ◽

Linxue Zhang ◽

JingChen Wen ◽

Mengyi Wang ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Hydrogen Sulphide ◽

Ring Finger ◽

Skeletal Muscle Atrophy

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Trimetazidine Attenuates Dexamethasone-Induced Muscle Atrophy via Inhibiting NLRP3/GSDMD Pathway-Mediated Pyroptosis

10.20944/preprints202012.0643.v1 ◽

2020 ◽

Author(s):

Li Wang ◽

Ming-Qing He ◽

Xi-Yu Shen ◽

Kang-Zhen Zhang ◽

Can Zhao ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Ring Finger ◽

Muscle Performance ◽

Skeletal Muscle Atrophy ◽

C2c12 Myotubes ◽

High Dose ◽

Therapeutic Compound

Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can also improve skeletal muscle performance both in human and mice. We here showed that dexamethasone induced atrophy, evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression , and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLRP3, Caspase-1 and GSDMD. Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine administration ameliorated dexamethasone-induced muscle atrophy both in vivo and in vitro. Moreover, trimetazidine improved exercise tolerance, as evidenced by increased running distance and running time, as well as increased skeletal muscle mass in dexamethasone-treated mice. Mechanically, trimetazidine could reverse dexamethasone-induced activation of pyroptosis both in C2C12 myotubes and in mice. Taken together, our present study demonstrated that NLRP3/GSDMD pathway-mediated pyroptosis was involved in dexamethasone-induced skeletal muscle atrophy. Trimetazidine could partially alleviate dexamethasone-induced skeletal muscle atrophy, and increase the diameter of C2C12 myotubes via inhibiting pyroptosis. Thus, trimetazidine might be a potential therapeutic compound for the prevention of muscle atrophy in glucocorticoid-treated patients.

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Chrysanthemi Zawadskii var. Latilobum Attenuates Obesity-Induced Skeletal Muscle Atrophy via Regulation of PRMTs in Skeletal Muscle of Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21082811 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2811

Author(s):

Ahyoung Yoo ◽

Young Jin Jang ◽

Jiyun Ahn ◽

Chang Hwa Jung ◽

Hyo Deok Seo ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Ring Finger ◽

Treadmill Running ◽

Skeletal Muscle Atrophy ◽

High Dose ◽

Obese Mice ◽

Protein Arginine Methyltransferases ◽

Protein Levels

As obesity promotes ectopic fat accumulation in skeletal muscle, resulting in impaired skeletal muscle and mitochondria function, it is associated with skeletal muscle loss and dysfunction. This study investigated whether Chrysanthemi zawadskii var. latilobum (CZH) protected mice against obesity-induced skeletal muscle atrophy and the underlying molecular mechanisms. High-fat diet (HFD)-induced obese mice were orally administered either distilled water, low-dose CZH (125 mg/kg), or high-dose CZH (250 mg/kg) for 8 w. CZH reduced obesity-induced increases in inflammatory cytokines levels and skeletal muscle atrophy, which is induced by expression of atrophic genes such as muscle RING-finger protein 1 and muscle atrophy F-box. CZH also improved muscle function according to treadmill running results and increased the muscle fiber size in skeletal muscle. Furthermore, CZH upregulated mRNA and protein levels of protein arginine methyltransferases (PRMT)1 and PRMT7, which subsequently attenuated mitochondrial dysfunction in the skeletal muscle of obese mice. We also observed that CZH significantly decreased PRMT6 mRNA and protein expression, which resulted in decreased muscle atrophy. These results suggest that CZH ameliorated obesity-induced skeletal muscle atrophy in mice via regulation of PRMTs in skeletal muscle.

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Zinc finger protein 593 is upregulated during skeletal muscle atrophy and modulates muscle cell differentiation

Experimental Cell Research ◽

10.1016/j.yexcr.2019.111563 ◽

2019 ◽

Vol 383 (2) ◽

pp. 111563 ◽

Cited By ~ 5

Author(s):

Sarah A. Lynch ◽

Marc A. McLeod ◽

Hannah C. Orsech ◽

Alexander M. Cirelli ◽

David S. Waddell

Keyword(s):

Skeletal Muscle ◽

Cell Differentiation ◽

Zinc Finger ◽

Muscle Cell ◽

Muscle Atrophy ◽

Zinc Finger Protein ◽

Skeletal Muscle Atrophy ◽

Muscle Cell Differentiation ◽

Finger Protein

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Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00204.2014 ◽

2014 ◽

Vol 307 (6) ◽

pp. E469-E484 ◽

Cited By ~ 355

Author(s):

Sue C. Bodine ◽

Leslie M. Baehr

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Striated Muscle ◽

Expression Patterns ◽

Ring Finger ◽

Physiological Role ◽

Ubiquitin Ligases ◽

Skeletal Muscle Atrophy ◽

E3 Ubiquitin Ligases ◽

Cellular Functions

Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy. In the past 10 years much has been published about MuRF1 and MAFbx with respect to their mRNA expression patterns under atrophy-inducing conditions, their transcriptional regulation, and their putative substrates. However, much remains to be learned about the physiological role of both genes in the regulation of mass and other cellular functions in striated muscle. Although both MuRF1 and MAFbx are enriched in skeletal, cardiac, and smooth muscle, this review will focus on the current understanding of MuRF1 and MAFbx in skeletal muscle, highlighting the critical questions that remain to be answered.

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