Beneficial Effects of Resveratrol in Mouse Gastrocnemius: A Hint to Muscle Phenotype and Proteolysis

We hypothesized that the phenolic compound resveratrol mitigates muscle protein degradation and loss and improves muscle fiber cross-sectional area (CSA) in gastrocnemius of mice exposed to unloading (7dI). In gastrocnemius of mice (female C57BL/6J, 10 weeks) exposed to a seven-day period of hindlimb immobilization with/without resveratrol treatment, markers of muscle proteolysis (tyrosine release, systemic troponin-I), atrophy signaling pathways, and muscle phenotypic features and function were analyzed. In gastrocnemius of unloaded mice treated with resveratrol, body and muscle weight and function were attenuated, whereas muscle proteolysis (tyrosine release), proteolytic and apoptotic markers, atrophy signaling pathways, and myofiber CSA significantly improved. Resveratrol treatment of mice exposed to a seven-day period of unloading prevented body and muscle weight and limb strength loss, while an improvement in muscle proteolysis, proteolytic markers, atrophy signaling pathways, apoptosis, and muscle fiber CSA was observed in the gastrocnemius muscle. These findings may have potential therapeutic implications in the management of disuse muscle atrophy in clinical settings.

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Muscle Phenotype, Proteolysis, and Atrophy Signaling During Reloading in Mice: Effects of Curcumin on the Gastrocnemius

Nutrients ◽

10.3390/nu12020388 ◽

2020 ◽

Vol 12 (2) ◽

pp. 388 ◽

Cited By ~ 3

Author(s):

Laura Mañas-García ◽

Nuria Bargalló ◽

Joaquim Gea ◽

Esther Barreiro

Keyword(s):

Protein Synthesis ◽

Signaling Pathways ◽

Muscle Function ◽

Histone Deacetylases ◽

Troponin I ◽

Muscle Protein ◽

Sirtuin 1 ◽

Hybrid Fibers ◽

Disuse Muscle Atrophy ◽

And Function

We hypothesized that curcumin may mitigate muscle protein degradation and loss through attenuation of proteolytic activity in limb muscles of mice exposed to reloading (7dR) following immobilization (7dI). In gastrocnemius of mice (female C57BL/6J, 10 weeks) exposed to recovery following a seven-day period of hindlimb immobilization with/without curcumin treatment, markers of muscle proteolysis (systemic troponin-I), atrophy signaling pathways and histone deacetylases, protein synthesis, and muscle phenotypic characteristics and function were analyzed. In gastrocnemius of reloading mice compared to unloaded, muscle function, structure, sirtuin-1, and protein synthesis improved, while proteolytic and signaling markers (FoxO1/3) declined. In gastrocnemius of unloaded and reloaded mice treated with curcumin, proteolytic and signaling markers (NF-kB p50) decreased and sirtuin-1 activity and hybrid fibers size increased (reloaded muscle), while no significant improvement was seen in muscle function. Treatment with curcumin elicited a rise in sirtuin-1 activity, while attenuating proteolysis in gastrocnemius of mice during reloading following a period of unloading. Curcumin attenuated muscle proteolysis probably via activation of histone deacetylase sirtuin-1, which also led to decreased levels of atrophy signaling pathways. These findings offer an avenue of research in the design of therapeutic strategies in clinical settings of patients exposed to periods of disuse muscle atrophy.

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Curcumin and Resveratrol Improve Muscle Function and Structure through Attenuation of Proteolytic Markers in Experimental Cancer-Induced Cachexia

Molecules ◽

10.3390/molecules26164904 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4904

Author(s):

Antonio Penedo-Vázquez ◽

Xavier Duran ◽

Javier Mateu ◽

Adrián López-Postigo ◽

Esther Barreiro

Keyword(s):

Signaling Pathways ◽

Muscle Wasting ◽

Troponin I ◽

Total Body Weight ◽

Sirtuin 1 ◽

Limb Muscle ◽

Cross Sectional ◽

Therapeutic Implications ◽

Beneficial Effects ◽

Muscle Mass Loss

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.

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Overload-mediated skeletal muscle hypertrophy is not impaired by loss of myofiber STAT3

AJP Cell Physiology ◽

10.1152/ajpcell.00100.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. C257-C261 ◽

Cited By ~ 8

Author(s):

Joaquín Pérez-Schindler ◽

Mary C. Esparza ◽

James McKendry ◽

Leigh Breen ◽

Andrew Philp ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Signal Pathways ◽

Muscle Weight ◽

Cross Sectional ◽

Adaptive Growth ◽

Stat3 Phosphorylation ◽

Transcription 3

Although the signal pathways mediating muscle protein synthesis and degradation are well characterized, the transcriptional processes modulating skeletal muscle mass and adaptive growth are poorly understood. Recently, studies in mouse models of muscle wasting or acutely exercised human muscle have suggested a potential role for the transcription factor signal transducer and activator of transcription 3 (STAT3), in adaptive growth. Hence, in the present study we sought to define the contribution of STAT3 to skeletal muscle adaptive growth. In contrast to previous work, two different resistance exercise protocols did not change STAT3 phosphorylation in human skeletal muscle. To directly address the role of STAT3 in load-induced (i.e., adaptive) growth, we studied the anabolic effects of 14 days of synergist ablation (SA) in skeletal muscle-specific STAT3 knockout (mKO) mice and their floxed, wild-type (WT) littermates. Plantaris muscle weight and fiber area in the nonoperated leg (control; CON) was comparable between genotypes. As expected, SA significantly increased plantaris weight, muscle fiber cross-sectional area, and anabolic signaling in WT mice, although interestingly, this induction was not impaired in STAT3 mKO mice. Collectively, these data demonstrate that STAT3 is not required for overload-mediated hypertrophy in mouse skeletal muscle.

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Troponin I Changes in Patients with Subarachnoid Hemorrhage

TAJ Journal of Teachers Association ◽

10.3329/taj.v27i2.37640 ◽

2018 ◽

Vol 27 (2) ◽

pp. 39-43

Author(s):

A Sarker ◽

MA Hoque ◽

MMR Khan ◽

MK Rahman ◽

SM Alam ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Troponin I ◽

Cardiac Injury ◽

Neurological Injury ◽

Enzyme Release ◽

College Hospital ◽

Cross Sectional ◽

Therapeutic Implications ◽

Patients At Risk ◽

Ctni Level

Background : Subarachnoid hemorrhage (SAH) is a catastrophic neurological event. Aside from its neurological morbidities, SAH is associated with significant medical complications. Cardiac manifestations are common and can impact morbidity and mortality in SAH patients. Myocardial enzyme release occur frequently after Subarachnoid hemorrhage that reflect adverse intracranial events .These changes often are unrecognized or misinterpreted, potentially placing patients at risk for inappropriate management.Objective : The aim of this study was to assess Troponin I changes after acute SAH and these changes were compared with neurological severity. The result of the study might be helpful for better understanding diagnostic and therapeutic implications of acute neurocardiogenic injury after SAH.Patients and methods : This cross sectional descriptive study was conducted over 30 patients with SAH in medicine, neuromedicine and intensive care unit of Rajshahi Medical College Hospital during the period of January 2015 to December 2016. Predictor variables reflecting demographic (age, sex, occupation), hemodynamic (pulse, systolic and diastolic blood pressure) and neurological (WFNS score) informations were recorded. We evaluated their cTnI level, which had been measured at admission. A cTnI level above 0.12 ng/ml was defined as an indicator of cardiac injury following SAH.Results : Out of 30 patients 26.7% were both in between 40-49 years and 60-69 years age group & 50% were male and 50% were female. Among the risk factors 60% of patient had history of hypertension, 40% smoking, 10% Diabetes mellitus and 3.3% alcohol abuse. On admission the mean GCS was 12.53±2.69,. The most frequently occurring WFNS grading were grade 1 and grade 4 (both were 43.3% of patients). Out of Thirty, 43.3% of patients demonstrated elevations of Troponin I. WFNS score ≥ 3 (92.3%, p = <0.001) significantly correlated with elevated Troponin I concentration.Conclusion : serum troponin I reveal a higher incidence of myocardial injury in patients with SAH. The present study also demonstrates that raised serum cTnI is associated with more severe neurological injury. These findings support a neurocardiogenic cause of cardiac injury after SAH.TAJ 2014; 27(2): 39-43

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Fiber number, area, and composition of mouse soleus muscle following enlargement

Journal of Applied Physiology ◽

10.1152/jappl.1985.58.2.619 ◽

1985 ◽

Vol 58 (2) ◽

pp. 619-624 ◽

Cited By ~ 31

Author(s):

B. F. Timson ◽

B. K. Bowlin ◽

G. A. Dudenhoeffer ◽

J. B. George

Keyword(s):

Muscle Fiber ◽

Soleus Muscle ◽

Histological Section ◽

Type I ◽

Muscle Weight ◽

Cross Sectional ◽

Male And Female ◽

Female Mice ◽

Fiber Area ◽

Fiber Number

Muscle fiber number, cross-sectional area, and composition were studied in response to enlargement produced by synergistic ablation in the mouse soleus muscle. The effect of the location of a histological section on the number of fibers that appear in the section was also studied using the mouse soleus muscle. Enlargement was produced in the soleus muscle of 15 male and 15 female mice by ablation of the ipsilateral gastrocnemius muscle. Fiber counts, using the nitric acid digestion method, revealed no difference between control and enlarged muscles in male and female mice. Mean fiber area, determined by planimetry, was 49.1 and 34.5% greater following enlargement in male and female mice, respectively. Increase in muscle weight could be totally accounted for by the increase in fiber area following enlargement. A transformation of type II to type I fibers occurred following enlargement for both sexes. Counts of fibers from histological sections revealed that there was a progressive decrease in the fiber number as the section was moved from the belly to the distal end of the muscle. The results of these studies indicate that muscle enlargement in the mouse soleus muscle is due to hypertrophy of the existing muscle fibers.

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Effects of aging, exercise, and disease on force transfer in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00095.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. E1-E10 ◽

Cited By ~ 32

Author(s):

David C. Hughes ◽

Marita A. Wallace ◽

Keith Baar

Keyword(s):

Skeletal Muscle ◽

Muscle Protein ◽

Injury Rate ◽

Cytoskeletal Proteins ◽

Neural Activation ◽

Force Transmission ◽

Cross Sectional ◽

Force Transfer ◽

Effects Of Aging ◽

And Function

The loss of muscle strength and increased injury rate in aging skeletal muscle has previously been attributed to loss of muscle protein (cross-sectional area) and/or decreased neural activation. However, it is becoming clear that force transfer within and between fibers plays a significant role in this process as well. Force transfer involves a secondary matrix of proteins that align and transmit the force produced by the thick and thin filaments along muscle fibers and out to the extracellular matrix. These specialized networks of cytoskeletal proteins aid in passing force through the muscle and also serve to protect individual fibers from injury. This review discusses the cytoskeleton proteins that have been identified as playing a role in muscle force transmission, both longitudinally and laterally, and where possible highlights how disease, aging, and exercise influence the expression and function of these proteins.

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The Haplolethal Region at the 16F Gene Cluster of Drosophila melanogaster: Structure and Function

Genetics ◽

10.1093/genetics/151.1.163 ◽

1999 ◽

Vol 151 (1) ◽

pp. 163-175 ◽

Cited By ~ 2

Author(s):

Antonio Prado ◽

Inmaculada Canal ◽

Alberto Ferrús

Keyword(s):

Drosophila Melanogaster ◽

Troponin I ◽

Muscle Protein ◽

Chromosomal Rearrangements ◽

Regulatory Region ◽

Lethal Effect ◽

Functional Expression ◽

Transcription Unit ◽

Dominant Lethal ◽

And Function

Abstract Extensive aneuploid analyses had shown the existence of a few haplolethal (HL) regions and one triplolethal region in the genome of Drosophila melanogaster. Since then, only two haplolethals, 22F1-2 and 16F, have been directly linked to identified genes, dpp and wupA, respectively. However, with the possible exception of dpp, the actual bases for this dosage sensitivity remain unknown. We have generated and characterized dominant-lethal mutations and chromosomal rearrangements in 16F and studied them in relation to the genes in the region. This region extends along 100 kb and includes at least 14 genes. The normal HL function depends on the integrity of a critical 4-kb window of mostly noncoding sequences within the wupA transcription unit that encodes the muscle protein troponin I (TNI). All dominant lethals are breakpoints within that window, which prevent the functional expression of TNI and other adjacent genes in the proximal direction. However, independent mutations in these genes result in recessive lethal phenotypes only. We propose that the HL at 16F represents a long-range cis regulatory region that acts upon a number of functionally related genes whose combined haploidy would yield the dominant-lethal effect.

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Electrical Stimulated Glut4 Signaling Attenuates Critical Illness-Associated Muscle Wasting

10.1101/2021.11.11.468054 ◽

2021 ◽

Author(s):

Alex Bernard Addinsall ◽

Nicola Cacciani ◽

Anders Backeus ◽

Yvette Hedstrom ◽

Lars Larsson

Keyword(s):

Critical Care ◽

Critical Illness ◽

Protein Degradation ◽

Soleus Muscle ◽

Muscle Wasting ◽

Muscle Protein ◽

Cross Sectional ◽

Controlled Mechanical Ventilation ◽

Muscle Protein Degradation ◽

And Function

Background: Critical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a byproduct of critical care, attributed to impaired recovery, longterm complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood, however loss of mechanical stimuli contributes to critical illness associated muscle atrophy and weakness. Passive mechanical loading (ML) and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care. Methods: Rats were subjected to 8 days critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and Western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM. Results: Following 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, Myosin:Actin ratio and single muscle fiber maximum force normalized to cross-sectional area (specific force) were reduced by 40-50% (p< 0.0001). ES significantly reduced the loss of soleus muscle fiber cross-sectional area (CSA) and Myosin:Actin ratio by approximately 30% (p< 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signaling in the soleus muscle following critical care and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (p< 0.01). ES promoted phosphofructokinase and insulin signaling pathways to control levels (p< 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signaling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (p= 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately 2-fold (p= 0.06). Reduction of muscle protein degradation rather than protein synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (p= 0.006) and MuRF1 (p= 0.08) by approximately 50%, downstream of AMPK-FoxO3. Conclusions: ES maintained GLUT4 translocation through increased AMPK-TBC1D4 signaling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signaling and reduced muscle protein degradation in CIM.

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Prolonged Immobilization Exacerbates the Loss of Muscle Mass and Function Induced by Cancer-Associated Cachexia through Enhanced Proteolysis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21218167 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8167

Author(s):

Laura Mañas-García ◽

Antonio Penedo-Vázquez ◽

Adrián López-Postigo ◽

Jorieke Deschrevel ◽

Xavier Durán ◽

...

Keyword(s):

Muscle Damage ◽

Muscle Mass ◽

Muscle Regeneration ◽

Troponin I ◽

Hindlimb Unloading ◽

Cross Sectional ◽

Muscle Mass Loss ◽

Prolonged Immobilization ◽

And Function ◽

Fast Twitch

We hypothesized that in mice with lung cancer (LC)-induced cachexia, periods of immobilization of the hindlimb (7 and 15 days) may further aggravate the process of muscle mass loss and function. Mice were divided into seven groups (n = 10/group): (1) non-immobilized control mice, (2) 7-day unloaded mice (7-day I), (3) 15-day unloaded mice (15-day I), (4) 21-day LC-cachexia group (LC 21-days), (5) 30-day LC-cachexia group (LC 30-days), (6) 21-day LC-cachexia group besides 7 days of unloading (LC 21-days + 7-day I), (7) 30-day LC-cachexia group besides 15 days of unloading (LC 30-days + 15-day I). Physiological parameters, body weight, muscle and tumor weights, phenotype and morphometry, muscle damage (including troponin I), proteolytic and autophagy markers, and muscle regeneration markers were identified in gastrocnemius muscle. In LC-induced cachexia mice exposed to hindlimb unloading, gastrocnemius weight, limb strength, fast-twitch myofiber cross-sectional area, and muscle regeneration markers significantly decreased, while tumor weight and area, muscle damage (troponin), and proteolytic and autophagy markers increased. In gastrocnemius of cancer-cachectic mice exposed to unloading, severe muscle atrophy and impaired function was observed along with increased muscle proteolysis and autophagy, muscle damage, and impaired muscle regeneration.

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Passive repetitive stretching is associated with greater muscle mass and cross-sectional area in the sarcopenic muscle

Scientific Reports ◽

10.1038/s41598-021-94709-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yumin Wang ◽

Satoshi Ikeda ◽

Katsunori Ikoma

Keyword(s):

Muscle Mass ◽

Gastrocnemius Muscle ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Fiber Type ◽

Cross Sectional Area ◽

Sectional Area ◽

Muscle Weight ◽

Cross Sectional ◽

Passive Stretching

AbstractMechanical stimulation has benefits for muscle mass and function. Passive stretching is widely performed in clinical rehabilitation medicine. However, the hypertrophic effects of passive repetitive stretching on senescent skeletal muscles against muscle atrophy remain unknown. We used senescence-accelerated model SAM-P8 mice. The gastrocnemius muscle was passively repetitive stretched by manual ankle dorsiflexion for 15 min, 5 days a week for 2 weeks under deep anesthesia. We examined the effects of passive stretching on muscle mass, myofiber cross-sectional area, muscle fiber type composition, satellite cell and myonuclei content, signaling pathways involved in muscle protein synthesis, and myogenic regulatory factors. The gastrocnemius muscle weight and fiber cross-sectional area of the stretched side was found greater compared with that of the unstretched side. Passive repetitive stretching increased the mRNA expression level of Akt, p70S6K, 4E-BP1, Myf5, myogenin, MuRF1.The phosphorylation level of p70S6K significantly increased in the stretched muscles, whereas of Akt and 4E-BP1 remained unchanged, compared to the unstretched side. The Pax7+ cells and myonuclei content did not differ between the stretched and unstretched muscles. These findings suggest that the hypertrophic or suppressed atrophic observation in the stretched muscles are mainly attributable to the protein turnover provoked by stretching. These findings are applicable to clinical muscle strengthening and sarcopenia prevention.

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