<i>Smad7</i>
            gene delivery prevents muscle wasting associated with cancer cachexia in mice

Winbanks, Catherine E.; Murphy, Kate T.; Bernardo, Bianca C.; Qian, Hongwei; Liu, Yingying; Sepulveda, Patricio V.; Beyer, Claudia; Hagg, Adam; Thomson, Russell; Chen, Justin L.; Walton, Kelly L.; Loveland, Kate; McMullen, Julie R.; Rodgers, Buel D.; Harrison, Craig A.; Lynch, Gordon S.; Gregorevic, Paul

doi:10.1126/scitranslmed.aac4976

Cited by 73 publications

(72 citation statements)

References 54 publications

(92 reference statements)

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“…Multiple factors, including inflammation cytokines, decreased food intake and neuroendocrine changes ( Oliff et al, 1987 ; Scott et al, 1996 ; Rivadeneira et al, 1999 ; Zhou et al, 2010 ; Sishi and Engelbrecht, 2011 ; Winbanks et al, 2016 ), contribute to the occurrence of cancer cachexia in vivo , which makes the mechanisms of cancer cachexia remain largely unknown. To make the question simple, here we used the in vitro system to investigate the mechanisms of PDTC on attenuating cancer cachexia.…”

Section: Resultsmentioning

confidence: 99%

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

Miao

Zhang

et al. 2017

Front. Pharmacol.

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Cancer cachexia is a kind of whole body metabolic disorder syndrome accompanied with severe wasting of muscle and adipose tissue. NF-κB signaling plays an important role during skeletal muscle atrophy and fat lipolysis. As an inhibitor of NF-κB signaling, Pyrrolidine dithiocarbamate (PDTC) was reported to relieve cancer cachexia; however, its mechanism remains largely unknown. In our study, we showed that PDTC attenuated cancer cachexia symptom in C26 tumor bearing mice models in vivo without influencing tumor volume. What’s more, PDTC inhibited muscle atrophy and lipolysis in cells models in vitro induced by TNFα and C26 tumor medium. PDTC suppressed atrophy of myotubes differentiated from C2C12 by reducing MyoD and upregulating MuRF1, and preserving the expression of perilipin as well as blocking the activation of HSL in 3T3-L1 mature adipocytes. Meaningfully, we observed that PDTC also inhibited p38 MAPK signaling besides the NF-κB signaling in cancer cachexia in vitro models. In addition, PDTC also influenced the protein synthesis of skeletal muscle by activating AKT signaling and regulated fat energy metabolism by inhibiting AMPK signaling. Therefore, PDTC primarily influenced different pathways in different tissues. The study not only established a simple and reliable screening drugs model of cancer cachexia in vitro but also provided new theoretical basis for future treatment of cancer cachexia.

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Section: Resultsmentioning

confidence: 99%

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

Miao

Zhang

et al. 2017

Front. Pharmacol.

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“…We have previously shown that increased circulating activins contribute to lean tissue loss in a number of cachexia models and that intracellular inhibition of Smad signaling, after gene delivery of the inhibitor Smad7, prevents muscle wasting associated with cachexia (42). In this study, we compared the therapeutic potential of the activin B and myostatin prodomains, alone and together, in the colon-26 (C26) model of cachexia (43).…”

Section: Discussionmentioning

confidence: 99%

Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

Chen

Walton

Hagg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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106

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Significance Myostatin, via activation of the Smad2/3 pathway, has long been recognized as the body’s major negative regulator of skeletal muscle mass. In this study, however, we demonstrate that other TGF-β proteins, particularly activin A and activin B, act in concert with myostatin to repress muscle growth. Preventing activin and myostatin signaling in the tibialis anterior muscles of mice resulted in massive hypertrophy (>150%), which was dependent upon both the complete inhibition of the Smad2/3 pathway and activation of the parallel bone morphogenetic protein (BMP)/Smad1/5 axis. Using this approach in models of muscular dystrophy and cancer cachexia increased muscle mass or prevented muscle wasting, respectively, highlighting the potential therapeutic advantages of complete inhibition of Smad2/3 ligand activity in skeletal muscle.

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“…Atrophy-associated genes and protein degradation. In many studies, the expression of various atrophy-associated genes, or "atrogenes," is used as a surrogate for protein degradation, especially the expression of those genes involved in the ubiquitin proteasome pathway (59). In this study, we examined the relationship between the expression of the four most commonly investigated atrophy-associated genes, i.e., MuRF1, MAFbx/atrogin-1, FOXO1, and FOXO3a, with proteasome activity.…”

Section: Discussionmentioning

confidence: 99%

Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

Baehr

West

Marshall

et al. 2017

Journal of Applied Physiology

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Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (-9 to -38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy.

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Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in mice

Cited by 73 publications

References 54 publications

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

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