Impaired regeneration: A role for the muscle microenvironment in cancer cachexia

Talbert, Erin E.; Guttridge, Denis C.

doi:10.1016/j.semcdb.2015.09.009

Cited by 56 publications

(43 citation statements)

References 173 publications

(180 reference statements)

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“…Muscle wasting in cancer cachexia can be attributed to decreased protein synthesis, impaired regeneration as well as increased protein degradation in skeletal muscle. At the time point in which body mass loss started to accelerate and predicted survival, increased mRNA expression of muscle specific E3 ubiquitin ligases and the content of ubiquitinated proteins were observed, suggesting increased protein degradation via the ubiquitin‐proteasome system.…”

Section: Discussionmentioning

confidence: 99%

“…Muscle wasting in cancer cachexia is a consequence of decreased muscle protein synthesis, impaired regeneration and/or increased protein degradation, but their relative importance and mechanisms are not well known. One possible mechanism for muscle wasting in cachexia is increased signalling through activin receptor ligands, such as myostatin and activins .…”

Section: Introductionmentioning

confidence: 99%

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Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Nissinen

Hentilä

Penna

et al. 2018

J cachexia sarcopenia muscle

162

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BackgroundCancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered.MethodsThe effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non‐muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B‐Fc). Treatment with sACVR2B‐Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non‐muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking.ResultsBlocking of ACVR2 ligands improved survival in tumour‐bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro‐inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B‐Fc was not explained by decreased markers of myeloid‐derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late‐endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis.ConclusionsThe prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non‐muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late‐endosomes in cancer opens up new research questions and possible treatment options for cachexia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Nissinen

Hentilä

Penna

et al. 2018

J cachexia sarcopenia muscle

162

View full text Add to dashboard Cite

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“…The most obvious of these and the most functionally consequential is wasting of skeletal muscle through activation of protein catabolism [125] and impaired myogenesis [126]. Adipose tissue inflammation is also observed, with wasting mediated through lipolytic and thermogenic processes [127].…”

Section: Systemic Inflammation In Cancer Cachexiamentioning

confidence: 99%

“…While much work has focused on protein homeostasis in cachexia, recent studies demonstrate accumulation of muscle progenitor cells, including satellite cells in murine and human cancer cachexia [126,148,149]. It is posited these cells are activated in response to cancer or cytokine-induced myocyte damage, but are unable to differentiate thereby contributing to muscle wasting by impaired nuclear accretion and loss of subsequent hypertrophic stimulus.…”

Section: 0 Stat3 In Skeletal Muscle Of Cancer Cachexiamentioning

confidence: 99%

STAT3 in the systemic inflammation of cancer cachexia

Zimmers

Fishel

Bonetto

2016

Seminars in Cell & Developmental Biology

194

166

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Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both contributory and protective functions for STAT3 in other organs during cachexia. Finally, STAT3 contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia in cancer and evidence for targeting STAT3 for anti-cachexia therapies.

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“…This may be influenced by lifestyle factors, which is corroborated by the tendency towards a difference in smoking status and blood lipid profile between the clusters. Alternatively, the molecular changes reflecting an early stage of muscle remodelling may originate from an impaired progression through regulating processes, preventing their late‐stage normalization, as may be the case for myogenesis . However, the drivers of differential clustering remain elusive and will be an important target for future investigations.…”

Section: Discussionmentioning

confidence: 99%

Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis

Kneppers

Haast

Langen

et al. 2019

J cachexia sarcopenia muscle

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Background Pulmonary rehabilitation (PR) is a cornerstone in the management of chronic obstructive pulmonary disease (COPD), targeting skeletal muscle to improve functional performance. However, there is substantial inter‐individual variability in the effect of PR on functional performance, which cannot be fully accounted for by generic phenotypic factors. We performed an unbiased integrative analysis of the skeletal muscle molecular responses to PR in COPD patients and comprehensively characterized their baseline pulmonary and physical function, body composition, blood profile, comorbidities, and medication use. Methods Musculus vastus lateralis biopsies were obtained from 51 COPD patients (age 64 ± 1 years, sex 73% men, FEV 1 , 34 (26–41) %pred.) before and after 4 weeks high‐intensity supervised in‐patient PR. Muscle molecular markers were grouped by network‐constrained clustering, and their relative changes in expression values—assessed by qPCR and western blot—were reduced to process scores by principal component analysis. Patients were subsequently clustered based on these process scores. Pre‐PR and post‐PR functional performance was assessed by incremental cycle ergometry and 6 min walking test (6MWT). Results Eight molecular processes were discerned by network‐constrained hierarchical clustering of the skeletal muscle molecular rehabilitation responses. Based on the resulting process scores, four clusters of patients were identified by hierarchical cluster analysis. Two major patient clusters differed in PR‐induced autophagy ( P < 0.001), myogenesis ( P = 0.014), glucocorticoid signalling ( P < 0.001), and oxidative metabolism regulation ( P < 0.001), with Cluster 1 (C1; n = 29) overall displaying a more pronounced change in marker expression than Cluster 2 (C2; n = 16). General baseline characteristics did not differ between clusters. Following PR, both 6 min walking distance (+26.5 ± 8.3 m, P = 0.003) and peak load on the cycle ergometer test (+9.7 ± 1.9 W, P < 0.001) were improved. However, the functional improvement was more pronounced in C1, as a higher percentage of patients exceeded the minimal clinically important difference in peak workload (61 vs. 21%, P = 0.022) and both peak workload and 6 min walking test (52 vs. 8%, P = 0.008) upon PR. Conclusions We identified patient groups with distinct skeletal muscle molecular responses to rehabilitation, associated with differences in functional improvements upon PR.

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Impaired regeneration: A role for the muscle microenvironment in cancer cachexia

Cited by 56 publications

References 173 publications

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

STAT3 in the systemic inflammation of cancer cachexia

Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis

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