Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

Sánchez, Brenda Janice; Tremblay, Ashley; Leduc‐Gaudet, Jean‐Philippe; Hall, Derek T; Kovács, Erzsébet Nagy; Jennifer, F.; Mubaid, Souad; Hallauer, Patricia L.; Phillips, Brittany L.; Vest, Katherine E.; Corbett, Anita H.; Kontoyiannis, Dimitris L.; Hussain, Sabah N. A.; Hastings, Kenneth E.M.; Marco, Sergio Di; Gallouzi, Imed Eddine

doi:10.1038/s41467-019-12186-6

Cited by 34 publications

(30 citation statements)

References 68 publications

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“…This is a trend that does not hold true for female animals, which show increases in RER relative to controls ( Figure 2 D). HuR m−/− male mice display RER values higher than controls at several time points when fed LFD, continuing to suggest an increased reliance on carbohydrates in agreement with previously reported results [ 6 , 17 ] ( Figure 2 E). No difference is present in RER patterns between genotypes for female animals fed LFD ( Figure 2 F).…”

Section: Resultssupporting

confidence: 92%

“…It was previously reported that HuR m−/− mice display increased energy expenditure relative to control animals, indicative of an increased oxidative phenotype in skeletal muscle [ 17 ]. HuR m−/− female mice fed HFD likewise show slightly higher energy expenditure relative to control females, but only during the day period while animals are not as active.…”

Section: Resultsmentioning

confidence: 99%

“…It has been previously reported that levels of Pparα, a transcription factor known to be an important promoter of lipid metabolism in skeletal muscle, were shown to be decreased in muscle of male HuR m−/− mice, which could contribute to decreased lipid oxidation [ 17 ]. However, HuR was also shown to have the capacity to destabilize mRNA for the metabolic regulator Pgc1α in skeletal muscle [ 17 ]. We used mRNA analysis to assay for changes in the levels of Pparα and Pgc1α in skeletal muscle in order to test the hypothesis that disruptions to these transcription factors may correlate with changes to skeletal muscle lipid oxidation.…”

Section: Resultsmentioning

confidence: 99%

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Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR

Stone

Noland

Mynatt

et al. 2021

Biology

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Male mice lacking HuR in skeletal muscle (HuRm−/−) have been shown to have decreased gastrocnemius lipid oxidation and increased adiposity and insulin resistance. The same consequences have not been documented in female HuRm−/− mice. Here we examine this sexually dimorphic phenotype. HuRm−/− mice have an increased fat mass to lean mass ratio (FM/LM) relative to controls where food intake is similar. Increased body weight for male mice correlates with increased blood glucose during glucose tolerance tests (GTT), suggesting increased fat mass in male HuRm−/− mice as a driver of decreased glucose clearance. However, HuRm−/− female mice show decreased blood glucose levels during GTT relative to controls. HuRm−/− mice display decreased palmitate oxidation in skeletal muscle relative to controls. This difference is more robust for male HuRm−/− mice and more exaggerated for both sexes at high dietary fat. A high-fat diet stimulates expression of Pgc1α in HuRm−/− male skeletal muscle, but not in females. However, the lipid oxidation Pparα pathway remains decreased in HuRm−/− male mice relative to controls regardless of diet. This pathway is only decreased in female HuRm−/− mice fed high fat diet. A decreased capacity for lipid oxidation in skeletal muscle in the absence of HuR may thus be linked to decreased glucose clearance in male but not female mice.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR

Stone

Noland

Mynatt

et al. 2021

Biology

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“…Interestingly, no selective fiber atrophy has been observed in a study of human patients with upper gastrointestinal or pancreatic cancer (30 men and 11 women) [ 51 ]. In a recent study [ 52 ] linking the RNA-binding protein, HuR, to fiber type specification demonstrates that while type 1 fiber-rich soleus muscle of male wild-type mice bearing the Lewis lung carcinoma was significantly wasted, muscle in the muscle-specific HuR knockout mice was preserved. The mechanism underlying the protective effect is through enrichment of type 1 fibers by HuR collaborating with the mRNA decay factor KSRP to destabilize PGC-1a mRNA.…”

Section: Sex-related Muscle Fiber Composition In Cancer Cachexiamentioning

confidence: 99%

Sex Differences in Cancer Cachexia

Zhong

Zimmers

2020

Curr Osteoporos Rep

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Purpose of Review Cachexia, a feature of cancer and other chronic diseases, is marked by progressive weight loss and skeletal muscle wasting. This review aims to highlight the sex differences in manifestations of cancer cachexia in patients, rodent models, and our current understanding of the potential mechanisms accounting for these differences. Recent Findings Male cancer patients generally have higher prevalence of cachexia, greater weight loss or muscle wasting, and worse outcomes compared with female cancer patients. Knowledge is increasing about sex differences in muscle fiber type and function, mitochondrial metabolism, global gene expression and signaling pathways, and regulatory mechanisms at the levels of sex chromosomes vs. sex hormones; however, it is largely undetermined how such sex differences directly affect the susceptibility to stressors leading to muscle wasting in cancer cachexia. Summary Few studies have investigated basic mechanisms underlying sex differences in cancer cachexia. A better understanding of sex differences would improve cachexia treatment in both sexes.

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“…Muscle atrophy is characterized by a decreased contractility of muscle fibers, changes in muscle fiber types and myosin subtypes, and a net loss of cytoplasm, organelles, and total proteins (Dumitru et al, 2018). In recent years, although research on denervated muscle atrophy has made substantial progress, it has mainly focused on single events, genes, or proteins (Li et al, 2017;Reza et al, 2017;Gueugneau et al, 2018;Yin et al, 2018;Castets et al, 2019;Janice Sánchez et al, 2019). Because systematic research on denervated muscle atrophy has not yet been conducted, no breakthrough has been achieved.…”

Section: Introductionmentioning

confidence: 99%

Isoquercitrin Delays Denervated Soleus Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation

et al. 2020

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Although denervated muscle atrophy is common, the underlying molecular mechanism remains unelucidated. We have previously found that oxidative stress and inflammatory response may be early events that trigger denervated muscle atrophy. Isoquercitrin is a biologically active flavonoid with antioxidative and anti-inflammatory properties. The present study investigated the effect of isoquercitrin on denervated soleus muscle atrophy and its possible molecular mechanisms. We found that isoquercitrin was effective in alleviating soleus muscle mass loss following denervation in a dose-dependent manner. Isoquercitrin demonstrated the optimal protective effect at 20 mg/kg/d, which was the dose used in subsequent experiments. To further explore the protective effect of isoquercitrin on denervated soleus muscle atrophy, we analyzed muscle proteolysis via the ubiquitinproteasome pathway, mitophagy, and muscle fiber type conversion. Isoquercitrin significantly inhibited the denervation-induced overexpression of two muscle-specific ubiquitin ligases-muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), and reduced the degradation of myosin heavy chains (MyHCs) in the target muscle. Following isoquercitrin treatment, mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy-related proteins (ATG7, BNIP3, LC3B, and PINK1); slow-to-fast fiber type conversion in the target muscle was delayed via triggering expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α); and the production of reactive oxygen species (ROS) in the target muscle was reduced, which might be associated with the upregulation of antioxidant factors (SOD1, SOD2, NRF2, NQO1, and HO1) and the downregulation of ROS production-related factors (Nox2, Nox4, and DUOX1). Furthermore, isoquercitrin treatment reduced the levels of inflammatory factors-interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α)-in the target muscle and inactivated the JAK/STAT3 signaling pathway. Overall, isoquercitrin may alleviate soleus muscle atrophy and mitophagy and reverse the slow-to-fast fiber type conversion following denervation via inhibition of oxidative stress and inflammatory response. Our study findings enrich the knowledge regarding the molecular regulatory mechanisms of denervated muscle atrophy and provide a scientific basis for isoquercitrin as a protective drug for the prevention and treatment of denervated muscle atrophy.

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Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

Cited by 34 publications

References 68 publications

Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR

Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR

Sex Differences in Cancer Cachexia

Isoquercitrin Delays Denervated Soleus Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation

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