Temporal disruption of neuromuscular communication and muscle atrophy following non-invasive ACL injury in rats

Many patients with anterior cruciate ligament (ACL) injuries have persistent quadriceps muscle atrophy, even after considerable time in rehabilitation. Understanding the factors that regulate muscle mass, and the time course of atrophic events, is important for identifying therapeutic interventions. Using a non-invasive animal model of ACL injury, a longitudinal study was performed to elucidate key parameters underlying quadriceps muscle atrophy. Male Long-Evans rats were euthanized at 6, 12, 24, 48-hrs and 1, 2, 4-wks after ACL injury that was induced via tibial compression overload; controls were not injured. Vastus Lateralis muscle size was determined by wet weight and fiber CSA. Evidence of disrupted neuromuscular communication was assessed via the expression of NCAM and genes associated with denervation and neuromuscular junction instability. Abundance of MuRF-1, MAFbx, and 45s pre-rRNA along with 20S proteasome activity were determined to investigate mechanisms related to muscle atrophy. Lastly, muscle damage-related parameters were assessed by measuring IgG permeability, centronucleation, CD68 mRNA and satellite cell abundance. Compared to controls, we observed a greater percentage of NCAM positive fibers at 6-hrs post-injury, followed by higher MAFbx abundance 48-hrs post-injury, and higher 20S proteasome activity at 1-wk post-injury. A loss of muscle wet weight, smaller fiber CSA and the elevated expression of Runx1 were also observed at the 1-wk post-injury time point relative to controls. There also were no differences observed in any damage markers. These results indicate that alterations in neuromuscular communication precede the upregulation of atrophic factors that regulate quadriceps muscle mass early after non-invasive ACL injury.

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The Study of Muscle, Mobility, and Aging (SOMMA): An Overview

Innovation in Aging ◽

10.1093/geroni/igab046.480 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 125-125

Author(s):

Steve Cummings ◽

Peggy Cawthon ◽

Russell Hepple

Keyword(s):

Muscle Mass ◽

Gait Speed ◽

Vastus Lateralis ◽

Cardiopulmonary Exercise Testing ◽

Quadriceps Muscle ◽

Biological Properties ◽

Vastus Lateralis Muscle ◽

Cognitive Assessments ◽

And Function ◽

Ancillary Studies

Abstract SOMMA is an NIA-funded cohort study to identify biological determinants of mobility and fitness. The overall aim of SOMMA is to use biopsies, novel biomarkers, advanced imaging, and intensive physical and cognitive assessments to elucidate the biological processes that contribute to changes in mobility and physical fitness with aging. SOMMA will recruit 875 people age 70+ (of whom about 200 have been enrolled.) We take biopsies of the vastus lateralis muscle to quantify mitochondrial content and function of the electron transport chain. We use 31PMR spectroscopy to quantify mitochondrial capacity to generate ATP in quadriceps muscle (ATPmax). We will quantify other biological properties in biopsies including denervation, autophagy and accumulated biochemical damage and use gene expression to discover pathways that contribute to mobility and fitness. SOMMA uses MR for quadriceps volume and D3Cr dilution for total skeletal muscle mass, cardiopulmonary exercise testing to measure fitness (VO2 peak). We are also making many other intensive assessments of physical and cognitive function. Mobility endpoints include baseline and three year change in 400 m and 4 meter gait speed and fitness. SOMMA is building a large biobank of muscle, adipose blood, and urine specimens that will be available for ancillary studies. In this Symposium, we will present results from analyses of associations between muscle mitochondrial function and strength, muscle mass, cognitive performance, gait speed, and fitness. The symposium will also preview opportunities for collaborations and ancillary studies with SOMMA.

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An antibody-based amperometric biosensor for 20S proteasome activity and inhibitor screening

The Analyst ◽

10.1039/d0an02426k ◽

2021 ◽

Cited By ~ 1

Author(s):

Madalina M. Barsan ◽

Victor C. Diculescu

Keyword(s):

Proteasome Activity ◽

Electrochemical Methods ◽

Amperometric Biosensor ◽

20S Proteasome ◽

Specific Interactions ◽

Inhibitor Screening

The 20S proteasome is immobilized through specific interactions with antibodies and its activity is evaluated by electrochemical methods.

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Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment

Scientific Reports ◽

10.1038/s41598-021-88392-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Risa Okada ◽

Shin-ichiro Fujita ◽

Riku Suzuki ◽

Takuto Hayashi ◽

Hirona Tsubouchi ◽

...

Keyword(s):

Gene Expression ◽

Muscle Mass ◽

Muscle Atrophy ◽

Transcriptome Analysis ◽

Fiber Type ◽

Expression Profiles ◽

Space Station ◽

Gene Expression Profiles

AbstractSpaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (μg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.

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Identification of Withania somnifera-Silybum marianum-Trigonella foenum-graecum Formulation as a Nutritional Supplement to Contrast Muscle Atrophy and Sarcopenia

Nutrients ◽

10.3390/nu13010049 ◽

2020 ◽

Vol 13 (1) ◽

pp. 49

Author(s):

Laura Salvadori ◽

Manuela Mandrone ◽

Tommaso Manenti ◽

Catia Ercolani ◽

Luca Cornioli ◽

...

Keyword(s):

Protein Kinase ◽

Muscle Mass ◽

Muscle Atrophy ◽

Withania Somnifera ◽

Myoblast Differentiation ◽

C2c12 Myotubes ◽

Silybum Marianum ◽

Trigonella Foenum Graecum ◽

Age Related

Background: Muscle atrophy, i.e., the loss of skeletal muscle mass and function, is an unresolved problem associated with aging (sarcopenia) and several pathological conditions. The imbalance between myofibrillary protein breakdown (especially the adult isoforms of myosin heavy chain, MyHC) and synthesis, and the reduction of muscle regenerative potential are main causes of muscle atrophy. Methods: Starting from one-hundred dried hydroalcoholic extracts of medical plants, we identified those able to contrast the reduction of C2C12 myotube diameter in well-characterized in vitro models mimicking muscle atrophy associated to inflammatory states, glucocorticoid treatment or nutrient deprivation. Based on their ability to rescue type II MyHC (MyHC-II) expression in atrophying conditions, six extracts with different phytochemical profiles were selected, mixed in groups of three, and tested on atrophic myotubes. The molecular mechanism underpinning the effects of the most efficacious formulation, and its efficacy on myotubes obtained from muscle biopsies of young and sarcopenic subjects were also investigated. Results: We identified WST (Withania somnifera, Silybum marianum, Trigonella foenum-graecum) formulation as extremely efficacious in protecting C2C12 myotubes against MyHC-II degradation by stimulating Akt (protein kinase B)-dependent protein synthesis and p38 MAPK (p38 mitogen-activated protein kinase)/myogenin-dependent myoblast differentiation. WST sustains trophism in C2C12 and young myotubes, and rescues the size, developmental MyHC expression and myoblast fusion in sarcopenic myotubes. Conclusion: WST strongly counteracts muscle atrophy associated to different conditions in vitro. The future validation in vivo of our results might lead to the use of WST as a food supplement to sustain muscle mass in diffuse atrophying conditions, and to reverse the age-related functional decline of human muscles, thus improving people quality of life and reducing social and health-care costs.

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Tail suspension is useful as a sarcopenia model in rats

Laboratory Animal Research ◽

10.1186/s42826-020-00083-9 ◽

2021 ◽

Vol 37 (1) ◽

Author(s):

Akira Nemoto ◽

Toru Goyagi

Keyword(s):

Skeletal Muscle ◽

Muscle Contraction ◽

Experimental Model ◽

Muscle Mass ◽

Muscle Atrophy ◽

Whole Body ◽

Skeletal Muscle Atrophy ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Simple Method

Abstract Background Sarcopenia promotes skeletal muscle atrophy and exhibits a high mortality rate. Its elucidation is of the highest clinical importance, but an animal experimental model remains controversial. In this study, we investigated a simple method for studying sarcopenia in rats. Results Muscle atrophy was investigated in 24-week-old, male, tail-suspended (TS), Sprague Dawley and spontaneously hypertensive rats (SHR). Age-matched SD rats were used as a control group. The skeletal muscle mass weight, muscle contraction, whole body tension (WBT), cross-sectional area (CSA), and Muscle RING finger-1 (MuRF-1) were assessed. Enzyme-linked immunosorbent assay was used to evaluate the MuRF-1 levels. Two muscles, the extensor digitorum longus and soleus muscles, were selected for representing fast and slow muscles, respectively. All data, except CSA, were analyzed by a one-way analysis of variance, whereas CSA was analyzed using the Kruskal-Wallis test. Muscle mass weight, muscle contraction, WBT, and CSA were significantly lower in the SHR (n = 7) and TS (n = 7) groups than in the control group, whereas MuRF-1 expression was dominant. Conclusions TS and SHR presented sarcopenic phenotypes in terms of muscle mass, muscle contraction and CSA. TS is a useful technique for providing muscle mass atrophy and weakness in an experimental model of sarcopenia in rats.

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Increasing autophagy does not affect neurogenic muscle atrophy

European Journal of Translational Myology ◽

10.4081/ejtm.2018.7687 ◽

2018 ◽

Vol 28 (3) ◽

Cited By ~ 5

Author(s):

Eva Pigna ◽

Krizia Sanna ◽

Dario Coletti ◽

Zhenlin Li ◽

Ara Parlakian ◽

...

Keyword(s):

Muscle Mass ◽

Muscle Atrophy ◽

Ubiquitin Proteasome System ◽

Autophagic Flux ◽

Molecular Pathways ◽

Muscle Loss ◽

Relative Contribution ◽

Ubiquitin Proteasome ◽

Muscle Mass Loss ◽

Kinetics Of

Physiological autophagy plays a crucial role in the regulation of muscle mass and metabolism, while the excessive induction or the inhibition of the autophagic flux contributes to the progression of several diseases. Autophagy can be activated by different stimuli, including cancer, exercise, caloric restriction and denervation. The latter leads to muscle atrophy through the activation of catabolic pathways, i.e. the ubiquitin-proteasome system and autophagy. However, the kinetics of autophagy activation and the upstream molecular pathways in denervated skeletal muscle have not been reported yet. In this study, we characterized the kinetics of autophagic induction, quickly triggered by denervation, and report the Akt/mTOR axis activation. Besides, with the aim to assess the relative contribution of autophagy in neurogenic muscle atrophy, we triggered autophagy with different stimuli along with denervation, and observed that four week-long autophagic induction, by either intermitted fasting or rapamycin treatment, did not significantly affect muscle mass loss. We conclude that: i) autophagy does not play a major role in inducing muscle loss following denervation; ii) nonetheless, autophagy may have a regulatory role in denervation induced muscle atrophy, since it is significantly upregulated as early as eight hours after denervation; iii) Akt/mTOR axis, AMPK and FoxO3a are activated consistently with the progression of muscle atrophy, further highlighting the complexity of the signaling response to the atrophying stimulus deriving from denervation.

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Predictors of changes in skeletal muscle mass after esophagectomy in elderly patients with esophageal cancer

10.21203/rs.3.rs-213862/v1 ◽

2021 ◽

Author(s):

Tsuyoshi Harada ◽

Noriatsu Tatematsu ◽

Junya Ueno ◽

Yu Koishihara ◽

Nobuko Konishi ◽

...

Keyword(s):

Skeletal Muscle ◽

Esophageal Cancer ◽

Elderly Patients ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Quadriceps Muscle ◽

Computed Tomography Images ◽

Ratio Change ◽

Comprehensive Rehabilitation ◽

The Mean

Abstract Purpose : Although a change in skeletal muscle mass index (SMI) 4 months after esophagectomy impacts prognosis, predictors of a change in SMI have not been revealed. The purpose of this exploratory retrospective study was to clarify the predictors of a change in SMI after curative esophagectomy in elderly patients with esophageal cancer.Methods : Fifty-four patients who underwent esophagectomy and perioperative rehabilitation from 2015 to 2018 were enrolled. Preoperative and postoperative SMI (cm 2 /m 2 ) were calculated using computed tomography images. The ratio change in SMI was calculated as follows: (postoperative SMI − preoperative SMI) ÷ preoperative SMI × 100%. Potential predictors of a change in SMI ratio were analyzed by multiple regression. Results : The mean ratio change in SMI 4 months after esophagectomy was −7.1% ± 9.4%. The ratio change in quadriceps muscle strength in the first month after surgery ([postoperative strength − preoperative strength] ÷ preoperative strength × 100%) (standardized β = .273, p = .038) and neoadjuvant chemotherapy (NAC) (standardized β = .398, p = .006) were predictors of the ratio change in SMI independent of age, sex, pathological stage, and preoperative SMI. Conclusion : Quadriceps muscle weakness in the first month after esophagectomy and NAC were predictors of the ratio change in SMI after esophagectomy. Continuous postoperative comprehensive rehabilitation and supportive care may inhibit loss of skeletal muscle mass.

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Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽

10.1371/journal.pgen.1010015 ◽

2022 ◽

Vol 18 (1) ◽

pp. e1010015

Author(s):

Cécile Ribot ◽

Cédric Soler ◽

Aymeric Chartier ◽

Sandy Al Hayek ◽

Rima Naït-Saïdi ◽

...

Keyword(s):

Muscular Dystrophy ◽

Muscle Atrophy ◽

Late Onset ◽

Oral Treatment ◽

Ubiquitin Proteasome System ◽

Proteasome Activity ◽

Functional Study ◽

Oculopharyngeal Muscular Dystrophy ◽

Ubiquitin Proteasome ◽

And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

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Glutamine prevents downregulation of myosin heavy chain synthesis and muscle atrophy from glucocorticoids

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.268.4.e730 ◽

1995 ◽

Vol 268 (4) ◽

pp. E730-E734 ◽

Cited By ~ 7

Author(s):

R. C. Hickson ◽

S. M. Czerwinski ◽

L. E. Wegrzyn

Keyword(s):

Protein Synthesis ◽

Myosin Heavy Chain ◽

Muscle Mass ◽

Muscle Atrophy ◽

Heavy Chain ◽

Total Protein ◽

Female Rats ◽

Glucocorticoid Treatment ◽

Precursor Pool ◽

Chain Synthesis

The aims of this study were to determine whether glutamine infusion prevents the decline in protein synthesis and muscle wasting associated with repeated glucocorticoid treatment. Hormone (cortisol acetate, 100 mg.kg body wt-1.day-1) and vehicle (carboxymethyl cellulose)-treated female rats were infused with either saline or glutamine (240 mM, 0.75 ml/h) for a 7-day period. Glutamine infusion attenuated the decline of plantaris muscle glutamine concentration (3.0 +/- 0.2 vs. 2.3 +/- 0.2 mumol/g) and prevented > 70% of the total muscle mass losses due to the glucocorticoid injections. Fractional synthesis rates of myosin heavy chain (MHC) and total protein were determined after constant [3H]leucine infusion from the leucyl-tRNA precursor pool, which was similar in all groups (range 4.8 +/- 0.5 to 6.3 +/- 0.4 disintegrations.min-1.pmol-1). MHC synthesis rates (%/day) in plantaris muscles were reduced to approximately 40% of controls (4.2/9.4). Although glutamine had no effect on MHC synthesis in vehicle-treated animals (10.1/9.4), it prevented 50% (7.6/4.2) of the hormone-induced decline in MHC synthesis rates. The same results were obtained with total protein synthesis measurements. Changes in muscle mass did not appear related to estimates of protein breakdown. In conclusion, these data show that glutamine infusion is effective therapy in counteracting glucocorticoid-induced muscle atrophy. Atrophy attenuation appears related to maintaining muscle glutamine levels, which in turn may limit the glucocorticoid-mediated downregulation of MHC synthesis.

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Expression Levels of Long Non-Coding RNAs Change in Models of Altered Muscle Activity and Muscle Mass

International Journal of Molecular Sciences ◽

10.3390/ijms21051628 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1628 ◽

Cited By ~ 3

Author(s):

Keisuke Hitachi ◽

Masashi Nakatani ◽

Shiori Funasaki ◽

Ikumi Hijikata ◽

Mizuki Maekawa ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Atrophy ◽

Skeletal Muscle Mass ◽

Muscle Size ◽

Skeletal Muscle Atrophy ◽

Myostatin Gene ◽

Expression Levels ◽

Non Coding Rnas

Skeletal muscle is a highly plastic organ that is necessary for homeostasis and health of the human body. The size of skeletal muscle changes in response to intrinsic and extrinsic stimuli. Although protein-coding RNAs including myostatin, NF-κβ, and insulin-like growth factor-1 (IGF-1), have pivotal roles in determining the skeletal muscle mass, the role of long non-coding RNAs (lncRNAs) in the regulation of skeletal muscle mass remains to be elucidated. Here, we performed expression profiling of nine skeletal muscle differentiation-related lncRNAs (DRR, DUM1, linc-MD1, linc-YY1, LncMyod, Neat1, Myoparr, Malat1, and SRA) and three genomic imprinting-related lncRNAs (Gtl2, H19, and IG-DMR) in mouse skeletal muscle. The expression levels of these lncRNAs were examined by quantitative RT-PCR in six skeletal muscle atrophy models (denervation, casting, tail suspension, dexamethasone-administration, cancer cachexia, and fasting) and two skeletal muscle hypertrophy models (mechanical overload and deficiency of the myostatin gene). Cluster analyses of these lncRNA expression levels were successfully used to categorize the muscle atrophy models into two sub-groups. In addition, the expression of Gtl2, IG-DMR, and DUM1 was altered along with changes in the skeletal muscle size. The overview of the expression levels of lncRNAs in multiple muscle atrophy and hypertrophy models provides a novel insight into the role of lncRNAs in determining the skeletal muscle mass.

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