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1.
Cytokine ; 159: 155972, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36054964

RESUMO

Musculoskeletal diseases such as muscular dystrophy, cachexia, osteoarthritis, and rheumatoid arthritis impair overall physical health and reduce survival. Patients suffer from pain, dysfunction, and dysmobility due to inflammation and fibrosis in bones, muscles, and joints, both locally and systemically. The Interleukin-6 (IL-6) family of cytokines, most notably IL-6, is implicated in musculoskeletal disorders and cachexia. Here we show elevated circulating levels of OSM in murine pancreatic cancer cachexia and evaluate the effects of the IL-6 family member, Oncostatin M (OSM), on muscle and bone using adeno-associated virus (AAV) mediated over-expression of murine OSM in wildtype and IL-6 deficient mice. Initial studies with high titer AAV-OSM injection yielded high circulating OSM and IL-6, thrombocytosis, inflammation, and 60% mortality without muscle loss within 4 days. Subsequently, to mimic OSM levels in cachexia, a lower titer of AAV-OSM was used in wildtype and Il6 null mice, observing effects out to 4 weeks and 12 weeks. AAV-OSM caused muscle atrophy and fibrosis in the gastrocnemius, tibialis anterior, and quadriceps of the injected limb, but these effects were not observed on the non-injected side. In contrast, OSM induced both local and distant trabecular bone loss as shown by reduced bone volume, trabecular number, and thickness, and increased trabecular separation. OSM caused cardiac dysfunction including reduced ejection fraction and reduced fractional shortening. RNA-sequencing of cardiac muscle revealed upregulation of genes related to inflammation and fibrosis. None of these effects were different in IL-6 knockout mice. Thus, OSM induces local muscle atrophy, systemic bone loss, tissue fibrosis, and cardiac dysfunction independently of IL-6, suggesting a role for OSM in musculoskeletal conditions with these characteristics, including cancer cachexia.


Assuntos
Cardiopatias , Interleucina-6 , Animais , Caquexia , Fibrose , Inflamação , Interleucina-6/farmacologia , Camundongos , Camundongos Knockout , Atrofia Muscular , Oncostatina M/farmacologia , RNA
2.
Basic Res Cardiol ; 112(4): 48, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28647906

RESUMO

Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.


Assuntos
Proteínas Morfogenéticas Ósseas/farmacologia , Caquexia/induzido quimicamente , Fatores de Diferenciação de Crescimento/farmacologia , Coração/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Miocárdio/patologia , Animais , Masculino , Camundongos , Camundongos Nus
3.
Nephrol Dial Transplant ; 31(2): 223-30, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26442903

RESUMO

BACKGROUND: The combination of skeletal muscle wasting and compromised function plays a role in the health decline commonly observed in chronic kidney disease (CKD) patients, but the pathophysiology of muscle mass/strength changes remains unclear. The purpose of this study was to characterize muscle properties in the Cy/+ rat model of spontaneously progressive CKD. METHODS: Leg muscle function and serum biochemistry of male Cy/+ (CKD) rats and their nonaffected littermates (NLs) were assessed in vivo at 25, 30 and 35 weeks of age. Architecture and histology of extensor digitorum longus (EDL) and soleus (SOL) muscles were assessed ex vivo at the conclusion of the experiment. We tested the hypothesis that animals with CKD have progressive loss of muscle function, and that this functional deficit is associated with loss of muscle mass and quality. RESULTS: Thirty-five-week-old CKD rats produced significantly lower maximum torque in ankle dorsiflexion and shorter time to maximum torque, and longer half relaxation time in dorsiflexion and plantarflexion compared with NL rats. Peak dorsiflexion torque (but not plantarflexion torque) in CKD remained steady from 25 to 35 weeks, while in NL rats, peak torque increased. Mass, physiologic cross-sectional area (CSA) and fiber-type (myosin heavy chain isoform) proportions of EDL and SOL were not different between CKD and NL. However, the EDL of CKD rats showed reduced CSAs in all fiber types, while only MyHC-1 fibers were decreased in area in the SOL. CONCLUSIONS: The results of this study demonstrate that muscle function progressively declines in the Cy/+ rat model of CKD. Because whole muscle mass and architecture do not vary between CKD and NL, but CKD muscles show reduction in individual fiber CSA, our data suggest that the functional decline is related to increased muscle fiber atrophy.


Assuntos
Contração Muscular , Músculo Esquelético/fisiopatologia , Atrofia Muscular , Cadeias Pesadas de Miosina/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Imuno-Histoquímica , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo
4.
J Exp Biol ; 218(Pt 2): 194-205, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25452499

RESUMO

Scratch-digging mammals are commonly described as having large, powerful forelimb muscles for applying high force to excavate earth, yet studies quantifying the architectural properties of the musculature are largely unavailable. To further test hypotheses about traits that represent specializations for scratch-digging, we quantified muscle architectural properties and myosin expression in the forelimb of the groundhog (Marmota monax), a digger that constructs semi-complex burrows. Architectural properties measured were muscle moment arm, muscle mass (MM), belly length (ML), fascicle length (l(F)), pennation angle and physiological cross-sectional area (PCSA), and these metrics were used to estimate maximum isometric force, joint torque and power. Myosin heavy chain (MHC) isoform composition was determined in selected forelimb muscles by SDS-PAGE and densitometry analysis. Groundhogs have large limb retractors and elbow extensors that are capable of applying moderately high torque at the shoulder and elbow joints, respectively. Most of these muscles (e.g. latissimus dorsi and pectoralis superficialis) have high l(F)/ML ratios, indicating substantial shortening ability and moderate power. The unipennate triceps brachii long head has the largest PCSA and is capable of the highest joint torque at both the shoulder and elbow joints. The carpal and digital flexors show greater pennation and shorter fascicle lengths than the limb retractors and elbow extensors, resulting in higher PCSA/MM ratios and force production capacity. Moreover, the digital flexors have the capacity for both appreciable fascicle shortening and force production, indicating high muscle work potential. Overall, the forelimb musculature of the groundhog is capable of relatively low sustained force and power, and these properties are consistent with the findings of a predominant expression of the MHC-2A isoform. Aside from the apparent modifications to the digital flexors, the collective muscle properties observed are consistent with its behavioral classification as a less-specialized burrower and these may be more representative of traits common to numerous rodents with burrowing habits or mammals with some fossorial ability.


Assuntos
Membro Anterior/anatomia & histologia , Membro Anterior/fisiologia , Marmota/anatomia & histologia , Animais , Fenômenos Biomecânicos , Feminino , Articulações/fisiologia , Masculino , Marmota/fisiologia , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiologia , Miosinas/análise , Isoformas de Proteínas/análise , Torque
6.
Immunometabolism (Cobham) ; 4(3): e00001, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35991116

RESUMO

Dysregulation of lipid deposition into and mobilization from white adipose tissue (WAT) underlies various diseases. Long-chain fatty acids (LCFA) and cholesterol trafficking in and out of adipocytes is a process relying on transporters shuttling lipids from the plasma membrane (PM) to lipid droplets (LD). CD36 is the fatty acid translocase (FAT) that transports LCFA and cholesterol across the PM. Interactions of CD36 with proteins PHB1, ANX2, and CAV1 mediate intercellular lipid transport between adipocytes, hematopoietic, epithelial, and endothelial cells. Intracellularly, the FAT complex has been found to regulate LCFA trafficking between the PM and LD. This process is regulated by CD36 glycosylation and S-acylation, as well as by post-translational modifications of PHB1 and ANX2, which determine both protein-protein interactions and the cellular localization of the complex. Changes in extracellular and intracellular LCFA levels have been found to induce the post-translational modifications and the function of the FAT complex in lipid uptake and mobilization. The role of the CD36/PHB1/ANX2 complex may span beyond lipid trafficking. The requirement of PHB1 for mitochondrial oxidative metabolism in brown adipocytes has been revealed. Cancer cells which take advantage of lipids mobilized by adipocytes and oxidized in leukocytes are indirectly affected by the function of FAT complex in other tissues. The direct importance of CD36 interaction with PHB1/and ANX2 in cancer cells remains to be established. This review highlights the multifaceted roles of the FAT complex in systemic lipid trafficking and discuss it as a potential target in metabolic disease and cancer.

7.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33851955

RESUMO

Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.


Assuntos
Caquexia/metabolismo , Caquexia/patologia , Interleucina-6/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Células 3T3 , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Lipólise/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Transdução de Sinais/fisiologia , Neoplasias Pancreáticas
8.
Shock ; 53(5): 605-615, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31939770

RESUMO

Trauma, burn injury, sepsis, and ischemia lead to acute and chronic loss of skeletal muscle mass and function. Healthy muscle is essential for eating, posture, respiration, reproduction, and mobility, as well as for appropriate function of the senses including taste, vision, and hearing. Beyond providing support and contraction, skeletal muscle also exerts essential roles in temperature regulation, metabolism, and overall health. As the primary reservoir for amino acids, skeletal muscle regulates whole-body protein and glucose metabolism by providing substrate for protein synthesis and supporting hepatic gluconeogenesis during illness and starvation. Overall, greater muscle mass is linked to greater insulin sensitivity and glucose disposal, strength, power, and longevity. In contrast, low muscle mass correlates with dysmetabolism, dysmobility, and poor survival. Muscle mass is highly plastic, appropriate to its role as reservoir, and subject to striking genetic control. Defining mechanisms of muscle growth regulation holds significant promise to find interventions that promote health and diminish morbidity and mortality after trauma, sepsis, inflammation, and other systemic insults. In this invited review, we summarize techniques and methods to assess and manipulate muscle size and muscle mass in experimental systems, including cell culture and rodent models. These approaches have utility for studies of myopenia, sarcopenia, cachexia, and acute muscle growth or atrophy in the setting of health or injury.


Assuntos
Modelos Biológicos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Ferimentos e Lesões/patologia , Ferimentos e Lesões/fisiopatologia , Técnicas de Cultura de Células , Simulação por Computador , Humanos , Ferimentos e Lesões/complicações
9.
Cancer Res ; 79(4): 699-700, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770364

RESUMO

Cancer cachexia remains a largely intractable, deadly condition for patients with no approved, effective therapies. However, research progress over the past few decades demonstrates that cachexia is a disease with specific, targetable mechanisms. New work by Murphy and colleagues in this issue of Cancer Research suggests that activation of the alternative renin-angiotensin system with the nonpeptide Mas receptor agonist AVE 0991 holds promise for reducing muscle wasting in cancer. Their cell studies demonstrate on-target activity in skeletal muscle cells, whereas their mouse results suggest potentially more important systemic effects.See related article by Murphy et al., p. 706.


Assuntos
Caquexia , Neoplasias , Animais , Humanos , Camundongos , Atrofia Muscular
10.
Sci Rep ; 9(1): 13903, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554905

RESUMO

Pannexins (Panxs), glycoproteins that oligomerize to form hemichannels on the cell membrane, are topologically similar to connexins, but do not form cell-to-cell gap junction channels. There are 3 members of the family, 1-3, with Panx1 being the most abundant. All Panxs are expressed in bone, but their role in bone cell biology is not completely understood. We now report that osteocytic Panx1 deletion (Panx1Δot) alters bone mass and strength in female mice. Bone mineral density after reaching skeletal maturity is higher in female Panx1Δot mice than in control Panx1fl/fl mice. Further, osteocytic Panx1 deletion partially prevented aging effects on cortical bone structure and mechanical properties. Young 4-month-old female Panx1Δot mice exhibited increased lean body mass, even though pannexin levels in skeletal muscle were not affected; whereas no difference in lean body mass was detected in male mice. Furthermore, female Panx1-deficient mice exhibited increased muscle mass without changes in strength, whereas Panx1Δot males showed unchanged muscle mass and decreased in vivo maximum plantarflexion torque, indicating reduced muscle strength. Our results suggest that osteocytic Panx1 deletion increases bone mass in young and old female mice and muscle mass in young female mice, but has deleterious effects on muscle strength only in males.


Assuntos
Osso e Ossos/metabolismo , Conexinas/metabolismo , Força Muscular/fisiologia , Músculo Esquelético/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteócitos/metabolismo , Animais , Índice de Massa Corporal , Feminino , Masculino , Camundongos , Doenças Musculares/metabolismo
11.
Anat Rec (Hoboken) ; 301(3): 434-440, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29418121

RESUMO

The musculoskeletal system is remarkably plastic during growth. The purpose of this study was to examine the muscular plasticity in functional and structural properties in a model known to result in significant developmental plasticity of the postcranial skeleton. Fifteen weanling C57BL/6 mice were raised to 16 weeks of age in one of two enclosures: a climbing enclosure that simulates a fine branch arboreal habitat and is traversed by steel wires crossing at 45° relative to horizontal at multiple intersections, and a control enclosure that resembles a parking deck with no wires but the same volume of habitable space. At killing, ex vivo contractility properties of the soleus (SOL) and extensor digitorum longus (EDL) muscles were examined. Our results demonstrate that EDL muscles of climbing mice contracted with higher specific forces and were comprised of muscle fibers with slower myosin heavy chain isoforms. EDL muscles also fatigued at a higher rate in climbing mice compared to controls. SOL muscle function is not affected by the climbing environment. Likewise, mass and architecture of both EDL and SOL muscles were not different between climbing and control mice. Our data demonstrate that functional adaptation does not require concomitant architectural adaptation in order to increase contractile force. Anat Rec, 301:434-440, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Aclimatação , Simulação por Computador , Ecossistema , Membro Posterior/fisiologia , Contração Muscular/fisiologia , Fibras Musculares de Contração Rápida/fisiologia , Fibras Musculares de Contração Lenta/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL
12.
J Vis Exp ; (117)2016 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-27929469

RESUMO

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2-4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3-5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification.


Assuntos
Caquexia/etiologia , Neoplasias do Colo , Modelos Animais de Doenças , Animais , Linhagem Celular Tumoral , Humanos , Interleucina-6 , Camundongos , Músculo Esquelético , Atrofia Muscular/etiologia , Reprodutibilidade dos Testes
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