Arrdc2 and Arrdc3 elicit divergent changes in gene expression in skeletal muscle following anabolic and catabolic stimuli

Bradley S. Gordon; Michael L. Rossetti; Alexey M. Eroshkin

doi:10.1152/physiolgenomics.00007.2019

Arrdc2 and Arrdc3 elicit divergent changes in gene expression in skeletal muscle following anabolic and catabolic stimuli

Physiological Genomics ◽

10.1152/physiolgenomics.00007.2019 ◽

2019 ◽

Vol 51 (6) ◽

pp. 208-217 ◽

Cited By ~ 2

Author(s):

Bradley S. Gordon ◽

Michael L. Rossetti ◽

Alexey M. Eroshkin

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Tibialis Anterior ◽

Gene Networks ◽

Tibialis Anterior Muscle ◽

The Body ◽

Molecular Networks ◽

Expression Of Genes ◽

Consistent Change ◽

Mechanical Overload

Skeletal muscle is a highly plastic organ regulating various processes in the body. As such, loss of skeletal muscle underlies the increased morbidity and mortality risk that is associated with numerous conditions. However, no therapies are available to combat the loss of muscle mass during atrophic conditions, which is due in part to the incomplete understanding of the molecular networks altered by anabolic and catabolic stimuli. Thus, the current objective was to identify novel gene networks modulated by such stimuli. For this, total RNA from the tibialis anterior muscle of mice that were fasted overnight or fasted overnight and refed the next morning was subjected to microarray analysis. The refeeding stimulus altered the expression of genes associated with signal transduction. Specifically, expression of alpha arrestin domain containing 2 (Arrdc2) and alpha arrestin domain containing 3 (Arrdc3) was significantly lowered 70–85% by refeeding. Subsequent analysis showed that expression of these genes was also lowered 50–75% by mechanical overload, with the combination of nutrients and mechanical overload acting synergistically to lower Arrdc2 and Arrdc3 expression. On the converse, stimuli that suppress growth such as testosterone depletion or acute aerobic exercise increased Arrdc2 and Arrdc3 expression in skeletal muscle. While Arrdc2 and Arrdc3 exhibited divergent changes in expression following anabolic or catabolic stimuli, no other member of the Arrdc family of genes exhibited the consistent change in expression across the analyzed conditions. Thus, Arrdc2 and Arrdc3 are a novel set of genes that may be implicated in the regulation of skeletal muscle mass.

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The Maintenance of Muscle Mass Is Independent of Testosterone in Adult Male Mice

10.1101/2020.09.24.311266 ◽

2020 ◽

Author(s):

Arik Davidyan ◽

Keith Baar ◽

Sue C. Bodine

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Tibialis Anterior ◽

Skeletal Muscle Mass ◽

Tibialis Anterior Muscle ◽

Male Mice ◽

Cross Sectional ◽

Western Blots ◽

Physiological Serum

AbstractTestosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, alterations in the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age; the age groups we used included 1.5-, 5-, 12-, and 24-month old mice. Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. 28 days of testosterone depletion resulted in smaller muscle mass in the two youngest cohorts but had no effect in the two older ones. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. We did not detect changes in protein synthesis at the terminal time point. This data suggest that within physiological serum concentrations, testosterone is not important for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.

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Maintenance of muscle mass in adult male mice is independent of testosterone

PLoS ONE ◽

10.1371/journal.pone.0240278 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0240278

Author(s):

Arik Davidyan ◽

Suraj Pathak ◽

Keith Baar ◽

Sue C. Bodine

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Tibialis Anterior ◽

Skeletal Muscle Mass ◽

Tibialis Anterior Muscle ◽

Male Mice ◽

Cross Sectional ◽

Western Blots ◽

Physiological Serum

Testosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be fully established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age (1.5-, 5-, 12-, and 24-month old mice). Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. Twenty-eight days of testosterone depletion resulted in reduced muscle mass in the two youngest cohorts, but had no effect in the two oldest cohorts. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. No change in protein synthesis was detected at the terminal time point. These data suggest that within physiological serum concentrations, testosterone may not be critical for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.

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Swim training affects Akt signaling and ameliorates loss of skeletal muscle mass in a mouse model of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-021-00319-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Karol Cieminski ◽

Damian Jozef Flis ◽

Katarzyna Dzik ◽

Jan Jacek Kaczor ◽

Emilia Czyrko ◽

...

Keyword(s):

Skeletal Muscle ◽

Signaling Pathway ◽

Muscle Mass ◽

Muscle Atrophy ◽

Skeletal Muscle Mass ◽

Tibialis Anterior Muscle ◽

Akt Signaling ◽

The Body ◽

Skeletal Muscle Atrophy ◽

Akt Signaling Pathway

AbstractWe tested the hypothesis that swim training reverses the impairment of Akt/FOXO3a signaling, ameliorating muscle atrophy in ALS mice. Transgenic male mice B6SJL-Tg (SOD1G93A) 1Gur/J were used as the ALS model (n = 35), with wild-type B6SJL (WT) mice as controls (n = 7). ALS mice were analyzed before ALS onset, at ALS onset, and at terminal ALS. Levels of insulin/Akt signaling pathway proteins were determined, and the body and tibialis anterior muscle mass and plasma creatine kinase. Significantly increased levels of FOXO3a in ALS groups (from about 13 to 21-fold) compared to WT mice were observed. MuRF1 levels in the ONSET untrained group (12.0 ± 1.7 AU) were significantly higher than in WT mice (1.12 ± 0.2 AU) and in the BEFORE ALS group (3.7 ± 0.9 AU). This was associated with body mass and skeletal muscle mass reduction. Swim training significantly ameliorated the reduction of skeletal muscle mass in both TERMINAL groups (p < 0.001) and partially reversed changes in the levels of Akt signaling pathway proteins. These findings shed light on the swimming-induced attenuation of skeletal muscle atrophy in ALS with possible practical implications for anti-cachexia approaches.

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Sarcopenia Diagnosis: Reliability of the Ultrasound Assessment of the Tibialis Anterior Muscle as an Alternative Evaluation Tool

Diagnostics ◽

10.3390/diagnostics11112158 ◽

2021 ◽

Vol 11 (11) ◽

pp. 2158

Author(s):

Massimiliano Leigheb ◽

Alessandro de Sire ◽

Matteo Colangelo ◽

Domenico Zagaria ◽

Federico Alberto Grassi ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Tibialis Anterior ◽

Tibialis Anterior Muscle ◽

Muscle Thickness ◽

Healthy Control Group ◽

Control Group ◽

Skeletal Muscle Index ◽

Healthy Control ◽

Ultrasound Assessment

Sarcopenia is a skeletal muscle disorder characterized by reduced muscle mass, strength, and performance. Muscle ultrasound can be helpful in assessing muscle mass, quality, and architecture, and thus possibly useful for diagnosing or screening sarcopenia. The objective of this study was to evaluate the reliability of ultrasound assessment of tibialis anterior muscle in sarcopenia diagnosis. We included subjects undergoing total or partial hip replacement, comparing measures with a healthy control group. We measured the following parameters: tibialis anterior muscle thickness, echogenicity, architecture, stiffness, skeletal muscle index (SMI), hand grip strength, and sarcopenia related quality of life evaluated through the SarQoL questionnaire. We included 33 participants with a mean age of 54.97 ± 23.91 years. In the study group we found reduced tibialis anterior muscle thickness compared to the healthy control group (19.49 ± 4.92 vs. 28.94 ± 3.63 mm, p < 0.05) with significant correlation with SarQoL values (r = 0.80, p < 0.05), dynamometer hand strength (r = 0.72, p < 0.05) and SMI (r = 0.76, p < 0.05). Moreover, we found reduced stiffness (32.21 ± 12.31 vs. 27.07 ± 8.04 Kpa, p < 0.05). AUC measures of ROC curves were 0.89 predicting reduced muscle strength, and 0.97 predicting reduced SMI for tibialis anterior muscle thickness, while they were 0.73 and 0.85, respectively, for muscle stiffness. Our findings showed that ultrasound assessment of tibialis anterior muscle might be considered a reliable measurement tool to evaluate sarcopenia.

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Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

Antioxidants ◽

10.3390/antiox10040588 ◽

2021 ◽

Vol 10 (4) ◽

pp. 588

Author(s):

Hayden W. Hyatt ◽

Scott K. Powers

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Chronic Diseases ◽

Muscle Mass ◽

Cancer Chemotherapy ◽

Muscle Wasting ◽

The Body ◽

Common Denominator ◽

Skeletal Muscle Wasting ◽

Vital Functions

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

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Structure of the cortical cytoskeleton in fibers of postural muscles and cardiomyocytes of mice after 30-day 2-g centrifugation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00812.2014 ◽

2015 ◽

Vol 118 (5) ◽

pp. 613-623 ◽

Cited By ~ 14

Author(s):

Irina V. Ogneva ◽

V. Gnyubkin ◽

N. Laroche ◽

M. V. Maximova ◽

I. M. Larina ◽

...

Keyword(s):

Skeletal Muscle ◽

Tibialis Anterior ◽

Mechanical Load ◽

Tibialis Anterior Muscle ◽

Muscle Fibers ◽

Control Group ◽

Negative Effects ◽

Transverse Stiffness ◽

G 12 ◽

Cortical Cytoskeleton

Altered external mechanical loading during spaceflights causes negative effects on muscular and cardiovascular systems. The aim of the study was estimation of the cortical cytoskeleton statement of the skeletal muscle cells and cardiomyocytes. The state of the cortical cytoskeleton in C57BL6J mice soleus, tibialis anterior muscle fibers, and left ventricle cardiomyocytes was investigated after 30-day 2- g centrifugation (“2- g” group) and within 12 h after its completion (“2- g + 12-h” group). We used atomic force microscopy for estimating cell's transverse stiffness, Western blotting for measuring protein content, and RT-PCR for estimating their expression level. The transverse stiffness significantly decreased in cardiomyocytes (by 16%) and increased in skeletal muscles fibers (by 35% for soleus and by 29% for tibialis anterior muscle fibers) in animals of the 2-g group (compared with the control group). For cardiomyocytes, we found that, in the 2- g + 12-h group, α-actinin-1 content decreased in the membranous fraction (by 27%) and increased in cytoplasmic fraction (by 28%) of proteins (compared with the levels in the 2- g group). But for skeletal muscle fibers, similar changes were noted for α-actinin-4, but not for α-actinin-1. In conclusion, we showed that the different isoforms of α-actinins dissociate from cortical cytoskeleton under increased/decreased of mechanical load.

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Change in skeletal muscle index and its prognostic significance in conversion therapy for initially unresectable colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.56 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 56-56

Author(s):

Hiroaki Nozawa ◽

Shigenobu Emoto ◽

Koji Murono ◽

Yasutaka Shuno ◽

Soichiro Ishihara

Keyword(s):

Colorectal Cancer ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscles ◽

Systemic Chemotherapy ◽

Stage Iv ◽

The Body ◽

Pharmacological Intervention ◽

Conversion Therapy ◽

Skeletal Muscle Index

56 Background: Systemic chemotherapy can cause loss of skeletal muscle mass in colorectal cancer (CRC) patients in the neoadjuvant and palliative settings. However, it is largely unknown how the body composition is changed by chemotherapy rendering unresectable CRC to resectable disease or how it affects the prognosis. This study aimed at elucidating the effects of systemic chemotherapy on skeletal muscles and survival in stage IV CRC patients who underwent conversion therapy. Methods: We reviewed 98 stage IV CRC patients who received systemic chemotherapy in our hospital. According to the treatment setting, patients were divided into the ‘Conversion’, ‘Neoadjuvant chemotherapy (NAC)’, and ‘Palliation’ groups. The cross-sectional area of skeletal muscles at the third lumbar level and changes in the skeletal muscle index (SMI), defined as the area divided by height squared, during chemotherapy were compared among patient groups. The effects of these parameters on prognosis were analyzed in the Conversion group. Results: The mean SMI increased by 8.0% during chemotherapy in the Conversion group (n = 38), whereas it decreased by 6.2% in the NAC group (n = 18) and 3.7% in the Palliation group (n = 42, p < 0.0001). Moreover, patients with increased SMI during chemotherapy had a better overall survival (OS) than those whose SMI decreased in the Conversion group (p = 0.021). The increase in SMI was an independent predictor of favorable OS on multivariate analysis (hazard ratio: 0.26). Conclusions: Stage IV CRC patients who underwent conversion to resection often had an increased SMI. As such an increase in SMI further conveys a survival benefit in conversion therapy, it may be important to make efforts to preserve muscle mass by meticulous approaches, such as nutritional support, muscle exercise programs, and pharmacological intervention even during chemotherapy in patients with metastatic CRC.

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Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism

AJP Cell Physiology ◽

10.1152/ajpcell.00432.2020 ◽

2021 ◽

Vol 320 (1) ◽

pp. C45-C56

Author(s):

David C. Hughes ◽

Daniel C. Turner ◽

Leslie M. Baehr ◽

Robert A. Seaborne ◽

Mark Viggars ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Ubiquitin Ligase ◽

Fluorescent Protein ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Tibialis Anterior Muscle ◽

E3 Ubiquitin Ligase ◽

Skeletal Muscle Atrophy ◽

The Impact

UBR5 is an E3 ubiquitin ligase positively associated with anabolism, hypertrophy, and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5’s role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in vivo. To achieve this aim, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle to investigate the impact of reduced UBR5 on anabolic signaling MEK/ERK/p90RSK and Akt/GSK3β/p70S6K/4E-BP1/rpS6 pathways. Seven days after UBR5 RNAi electroporation, although reductions in overall muscle mass were not detected, the mean cross-sectional area (CSA) of green fluorescent protein (GFP)-positive fibers were reduced (−9.5%) and the number of large fibers were lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2, Akt, and GSK3β activity. Although p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (−4.6%) and larger reductions in fiber CSA (−18.5%) after 30 days. This was associated with increased levels of phosphatase PP2Ac and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, as well as corresponding reductions in eIF4e. This study demonstrates that UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.

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The Association between Serum Uric Acid and Appendicular Skeletal Muscle Mass and the Effect of Their Interaction on Mortality in Patients on Peritoneal Dialysis

Kidney & Blood Pressure Research ◽

10.1159/000510746 ◽

2020 ◽

Vol 45 (6) ◽

pp. 969-981

Author(s):

Xi Xiao ◽

Chunyan Yi ◽

Yuan Peng ◽

Hongjian Ye ◽

Haishan Wu ◽

...

Keyword(s):

Skeletal Muscle ◽

Uric Acid ◽

Peritoneal Dialysis ◽

Serum Uric Acid ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

The Body ◽

All Cause Mortality ◽

Appendicular Skeletal Muscle ◽

Appendicular Skeletal Muscle Mass

Background: Serum uric acid (SUA) has been revealed to be positively associated with the body composition parameters in hemodialysis patients, but few studies have investigated that in patients on peritoneal dialysis (PD). The aim of this study was to identify the relationship between SUA and appendicular skeletal muscle mass (ASM) and the effect of their interaction on mortality in PD patients. Methods: This was a single-center retrospective cohort study. Patients who underwent multifrequency bioelectrical impedance analysis between January 1, 2013, and December 31, 2016, and had data on SUA values were enrolled. All patients were followed up until December 31, 2019. Results: In total, 802 prevalent PD patients (57.9% male), with mean age of 46.2 ± 14.2 years were enrolled. The average SUA and ASM were 6.8 ± 1.3 mg/dL and 21.2 ± 4.9 kg. According to multiple linear regression models, SUA was positively associated with relative ASM in middle-aged and older PD patients (standardized coefficients [β] 0.117; 95% confidence interval [CI] 0.027, 0.200; p = 0.010). Further sex-stratified analysis showed that the association existed only in males (β 0.161; 95% CI 0.017, 0.227; p = 0.023). Moreover, the presence of hyperuricemia was found to predict lower risk of all-cause mortality (hazard ratio [HR] 0.514, 95% CI 0.272, 0.970; p = 0.040) only in patients with lower relative ASM. And, the adjusted HR of every 1 mg/dL elevated SUA level was 0.770 (95% CI 0.609, 0.972; p = 0.028) for all-cause mortality in the lower relative ASM subgroup. Conclusions: There exists a positive association between the SUA and ASM, and the ASM significantly affected the association between SUA and all-cause PD mortality.

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