Altered expression of skeletal muscle myosin isoforms in cancer cachexia

2002 ◽  
Vol 283 (5) ◽  
pp. C1376-C1382 ◽  
Author(s):  
Gary M. Diffee ◽  
Katherine Kalfas ◽  
Sadeeka Al-Majid ◽  
Donna O. McCarthy
Keyword(s):  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Tumor Cell Line ◽  
Protein Isoforms ◽  
Type I ◽  
Myosin Isoforms ◽  
Skeletal Muscle Myosin ◽  
Altered Expression ◽  
Isoform Expression

Cachexia is commonly seen in cancer and is characterized by severe muscle wasting, but little is known about the effect of cancer cachexia on expression of contractile protein isoforms such as myosin. Other causes of muscle atrophy shift expression of myosin isoforms toward increased fast (type II) isoform expression. We injected mice with murine C-26 adenocarcinoma cells, a tumor cell line that has been shown to cause muscle wasting. Mice were killed 21 days after tumor injection, and hindlimb muscles were removed. Myosin heavy chain (MHC) and myosin light chain (MLC) content was determined in muscle homogenates by SDS-PAGE. Body weight was significantly lower in tumor-bearing (T) mice. There was a significant decrease in muscle mass in all three muscles tested compared with control, with the largest decrease occurring in the soleus. Although no type IIb MHC was detected in the soleus samples from control mice, type IIb comprised 19% of the total MHC in T soleus. Type I MHC was significantly decreased in T vs. control soleus muscle. MHC isoform content was not significantly different from control in plantaris and gastrocnemius muscles. These data are the first to show a change in myosin isoform expression accompanying muscle atrophy during cancer cachexia.

MHC and sarcoplasmic reticulum protein isoforms in functionally overloaded cat plantaris muscle fibers

1996 ◽  
Vol 80 (4) ◽  
pp. 1296-1303 ◽  
Author(s):  
R. J. Talmadge ◽  
R. R. Roy ◽  
G. R. Chalmers ◽  
V. R. Edgerton
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Heavy Chain ◽  
Muscle Fibers ◽  
Protein Isoforms ◽  
Type I ◽  
Single Muscle ◽  
Plantaris Muscle ◽  
Plasmic Reticulum ◽  
Deep Region ◽  
Isoform Expression

To determine whether the adaptations in myosin heavy chain (MHC) isoform expression after functional overload (FO) are accompanied by commensurate adaptations in protein isoforms responsible for relaxation [sarco(endo)plasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (SERCA) and phospholamban (PHL)] in single muscle fibers, the isoforms of MHC and SERCA and the presence or absence of PHL were determined for cat plantaris fibers 3 mo after FO. In control plantaris the relative MHC isoform composition was 23% type I, 21% type IIa, and 56% type IIb. FO resulted in a shift toward slower isoforms (33% type I, 44% type IIa, and 23% type IIb). In the deep region of the plantaris the proportions of type I MHC and hybrid MHC fibers (containing type I and II MHCs) were 40 and 200% greater in FO cats, respectively. FO resulted in a 47% increase in the proportion of fibers containing only the slow SERCA isoform (SERCA2) and a 41% increase in the proportion of fibers containing PHL. The proportions of fibers containing type I MHC, SERCA2, and PHL in control and FO plantaris were linearly correlated. These data show that adaptations in MHC isoform expression are accompanied by commensurate adaptations in sarcoplasmic reticulum protein isoforms in single muscle fibers after FO.

scholarly journals Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lin Zhou ◽  
Tong Zhang ◽  
Wei Shao ◽  
Ruohan Lu ◽  
Lin Wang ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Drug Repositioning ◽  
Biochemical Analyses ◽  
Related Proteins ◽  
Metabolic Impairments

Abstract Background Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia. Methods The CT26 and LLC tumor cells were subcutaneously injected into mice to induce colon cancer cachexia and lung cancer cachexia, respectively. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 model and the LLC model were separately characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results The CT26 and LLC cachexia models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue, and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. Both the CT26 and LLC cachexia mice showed increased plasma exosome densities which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis, and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions Amiloride ameliorates cachectic muscle wasting and alleviates cancer cachexia progression through inhibiting tumor-derived exosome release. Our results are beneficial to understanding the underlying molecular mechanisms, shedding light on the potentials of amiloride in cachexia therapy.

scholarly journals Neurohypophyseal hormones and skeletal muscle: a tale of two faces

2020 ◽  
Vol 30 (1) ◽  
pp. 53-57
Author(s):  
Alexandra Benoni ◽  
Alessandra Renzini ◽  
Giorgia Cavioli ◽  
Sergio Adamo
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Striated Muscle ◽  
Cardiac Atrophy ◽  
Neurohypophyseal Hormones

The neurohypophyseal hormones vasopressin and oxytocin were invested, in recent years, with novel functions upon striated muscle, regulating its differentiation, trophism, and homeostasis. Recent studies highlight that these hormones not only target skeletal muscle but represent novel myokines. We discuss the possibility of exploiting the muscle hypertrophying activity of oxytocin to revert muscle atrophy, including cancer cachexia muscle wasting. Furthermore, the role of oxytocin in cardiac homeostasis and the possible role of cardiac atrophy as a concause of death in cachectic patients is discussed.

Microgravity-induced transformations of myosin isoforms and contractile properties of skeletal muscle

1996 ◽  
Vol 81 (1) ◽  
pp. 123-132 ◽  
Author(s):  
V. J. Caiozzo ◽  
F. Haddad ◽  
M. J. Baker ◽  
R. E. Herrick ◽  
N. Prietto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Level ◽  
Muscle Fibers ◽  
Contractile Properties ◽  
Protein Isoforms ◽  
Control Group ◽  
Type I ◽  
Myosin Isoforms ◽  
Force Frequency ◽  
Mrna Isoform

This study examined the effects of microgravity (14 days) on 1) the contractile properties of the soleus (Sol), an antigravity skeletal muscle; and 2) the myosin heavy chain (MHC) protein and mRNA isoform content of the Sol, vastus intermedius (VI), plantaris (Plan), and tibialis anterior (TA) muscles. The force-velocity relationships of the flight Sol muscles had a significant reduction in maximal isometric tension (-37%) and a corresponding increase in maximal shortening velocity (+20%). Additionally, the force-frequency relationship of the flight Sol muscles was shifted to the right of the ground-based control group. Microgravity had the greatest effect on muscle fiber composition in the Sol muscle, with a reduction in slow muscle fibers and a corresponding increase in muscle fibers categorized as hybrid fibers. The estimated absolute MHC isoform content was altered to the greatest extent in the Sol and VI muscles, with significant decreases and elevations in the slow type I and fast type IIX MHC protein isoforms, respectively. Consistent with the protein data, both the flight Sol and VI muscles exhibited significant elevations in the fast type IIX MHC mRNA isoform. In contrast, however, the flight Plan and TA groups had significant increases in the fast type IIB MHC mRNA isoform content without corresponding changes at the protein level. The results of this study suggest that spaceflight of even short duration produces important changes in the contractile properties of antigravity skeletal muscle. These changes are mediated by alterations in MHC phenotype and reductions in muscle mass. In some instances, the alterations in MHC mRNA isoform content seemed to be uncoupled from those occurring at the protein level. This apparent uncoupling between mRNA and protein expression demonstrates that the effects of microgravity must be better understood at the transcriptional, translational, and post-translational levels.

scholarly journals Transcriptome Analysis of Skeletal Muscle Reveals Altered Proteolytic and Neuromuscular Junction Associated Gene Expressions in a Mouse Model of Cerebral Ischemic Stroke

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 726
Author(s):  
Peter J. Ferrandi ◽  
Mohammad Moshahid Khan ◽  
Hector G. Paez ◽  
Christopher R. Pitzer ◽  
Stephen E. Alway ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Neuromuscular Junction ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Altered Expression ◽  
Post Stroke ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that induces muscle wasting and weakness, which predominantly contribute to functional disability in stroke patients. Currently, no pharmacological drug is available to treat post-stroke muscle morbidities as the mechanisms underlying post-stroke muscle wasting remain poorly understood. To understand the stroke-mediated molecular changes occurring at the transcriptional level in skeletal muscle, the gene expression profiles and enrichment pathways were explored in a mouse model of cerebral ischemic stroke via high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq revealed that the elevated muscle atrophy observed in response to stroke was associated with the altered expression of genes involved in proteolysis, cell cycle, extracellular matrix remodeling, and the neuromuscular junction (NMJ). These data suggest that stroke primarily targets muscle protein degradation and NMJ pathway proteins to induce muscle atrophy. Collectively, we for the first time have found a novel genome-wide transcriptome signature of post-stroke skeletal muscle in mice. Our study will provide critical information to further elucidate specific gene(s) and pathway(s) that can be targeted to mitigate accountable for post-stroke muscle atrophy and related weakness.

scholarly journals The mechanism by which noncoding RNAs regulate muscle wasting in cancer cachexia

2021 ◽  
Author(s):  
Xueer Zhou ◽  
Shoushan Hu ◽  
Yunan Zhang ◽  
Guannan Du ◽  
Yi Li
Keyword(s):  
Metabolic Syndrome ◽  
Muscle Atrophy ◽  
Intercellular Communication ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Expression Profiles ◽  
Noncoding Rnas ◽  
Diagnostic Methods ◽  
Novel Therapies ◽  
Patients With Cancer

Abstract Cancer cachexia (CC) is a subject of concern because it is a complex metabolic syndrome that accelerates muscle wasting and affects up to 80% of patients with cancer; however, timely diagnostic methods and effective cures are lacking. Although a considerable number of studies have focused on the mechanism of CC-induced muscle atrophy, few novel therapies have been applied in the last decade. In recent years, noncoding RNAs (ncRNAs) have attracted great attention since many differentially expressed ncRNAs in cancer cachectic muscles have been reported to participate in the inhibition of myogenesis and activation of proteolysis. In addition, extracellular vesicles (EVs), which function as ncRNA carriers in intercellular communication, are closely involved in changing ncRNA expression profiles in muscle and promoting the development of muscle wasting; thus, EV-related ncRNAs may represent potential therapeutic targets. This review comprehensively describes the process of ncRNA transmission through EVs and summarizes the pathways and targets of ncRNAs that lead to CC-induced muscle atrophy.

scholarly journals Lithium Chloride Protects against Sepsis-Induced Skeletal Muscle Atrophy and Cancer Cachexia

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1017
Author(s):  
Ji-Hyung Lee ◽  
Seon-Wook Kim ◽  
Jun-Hyeong Kim ◽  
Hyun-Jun Kim ◽  
JungIn Um ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Lithium Chloride ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Therapeutic Effects ◽  
In Vivo Models ◽  
Skeletal Muscle Wasting ◽  
Chloride Treatment

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia.

scholarly journals The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis

2019 ◽  
Vol 20 (8) ◽  
pp. 1962 ◽  
Author(s):  
Paula Paccielli Freire ◽  
Geysson Javier Fernandez ◽  
Sarah Santiloni Cury ◽  
Diogo de Moraes ◽  
Jakeline Santos Oliveira ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differentially Expressed Genes ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Meta Analysis ◽  
Therapeutic Strategies ◽  
Expression Data ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%–80% of cancer patients, depending on the tumor type, and is associated with 20%–40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy—a key feature in cancer cachexia—no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA–mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA–mRNA interactions, such as miR-27a/Foxo1, miR-27a/Mef2c, miR-27b/Cxcl12, miR-27b/Mef2c, miR-140/Cxcl12, miR-199a/Cav1, and miR-199a/Junb, which may contribute to muscle wasting in cancer cachexia. Finally, we found drugs targeting MSTN, CXCL12, and CAMK2B, which may be considered for the development of novel therapeutic strategies for cancer cachexia. Our study has broadened the knowledge of microRNA-regulated networks that are likely associated with muscle atrophy in cancer cachexia, pointing to their involvement as potential targets for novel therapeutic strategies.

IGF-1 is downregulated in experimental cancer cachexia

2006 ◽  
Vol 291 (3) ◽  
pp. R674-R683 ◽  
Author(s):  
Paola Costelli ◽  
Maurizio Muscaritoli ◽  
Maurizio Bossola ◽  
Fabio Penna ◽  
Patrizia Reffo ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Signal Transduction Pathway ◽  
Ubiquitin Proteasome System ◽  
Underlying Mechanism ◽  
Simple Relation ◽  
Mrna Levels ◽  
Experimental Conditions ◽  
Skeletal Muscle Wasting

Cancer cachexia is characterized by skeletal muscle wasting that is mainly supported by hypercatabolism. Muscle atrophy has been suggested to depend on impaired IGF-1 signal transduction pathway. The present study has been aimed at investigating the IGF-1 system in rats bearing the AH-130 hepatoma, a well-characterized model of cachexia. IGF-1 mRNA expression in the gastrocnemius of tumor hosts progressively decreases to ∼50% of controls. By contrast, both IGF-1 receptor and insulin receptor mRNA levels increase in day 7 AH-130 hosts. IGF-1 and insulin circulating levels, as well as IGF-1 expression in the liver, are reduced. Muscle wasting in the AH-130 bearers is associated with hyperactivation of the ubiquitin-proteasome system. Consistently, the mRNA levels of ubiquitin and of the ubiquitin ligases atrogin-1 and MuRF1 are significantly increased in the gastrocnemius of day 7 AH-130 hosts. Exogenous IGF-1 administered to tumor bearers does not prevent cachexia. IGF-1 mRNA levels also have been evaluated in the gastrocnemius of AH-130 hosts treated with pentoxifylline, an inhibitor of TNF-α synthesis, alone or combined with formoterol, a β2-adrenergic agonist. Both treatments partially correct muscle atrophy without modifying IGF-1 and atrogin-1 mRNA levels, whereas MuRF1 hyperexpression is reduced by the combination of pentoxifylline with formoterol. These results demonstrate for the first time that the IGF-1 system is downregulated in cancer cachexia, although the underlying mechanism remains unknown. Moreover, no simple relation linking IGF-1 and/or atrogin-1 mRNA levels and muscle atrophy could be observed in these experimental conditions. Further studies are thus needed to clarify both issues.

Competitive control of myosin expression: hypertrophy vs. hyperthyroidism

1991 ◽  
Vol 70 (5) ◽  
pp. 2328-2330 ◽  
Author(s):  
C. D. Ianuzzo ◽  
N. Hamilton ◽  
B. Li
Keyword(s):  
Skeletal Muscle ◽  
Phenotypic Expression ◽  
Compensatory Hypertrophy ◽  
Surgical Removal ◽  
Type I ◽  
Myosin Isoforms ◽  
Skeletal Muscle Myosin ◽  
Slow Myosin ◽  
Fast Myosin ◽  
Muscle Myosin

The competition between two opposing influences on the phenotypic expression of skeletal muscle myosin were studied to determine which was the dominant regulator. Experimental hyperthyroidism, which induces fast myosin expression, was produced by subcutaneous implantation of a 40-day constant-time-release triiodothyronine pellet. Compensatory hypertrophy, which induces slow myosin expression, was produced by surgical removal of a synergistic hindlimb muscle. Hyperthyroidism increased the percentage of type II fibers and the fast myosin isoforms in both the plantaris and soleus muscles. Hypertrophy significantly increased the percentage of type I fibers and the slow myosin type in the plantaris and soleus muscles. However, with the simultaneous introduction of hyperthyroidism and hypertrophy, only the hyperthyroid effects were observed. Hyperthyroidism and not physiological demand was found to be the dominant regulator of skeletal muscle myosin expression.

Sign in / Sign up

Export Citation Format

Share Document