Iron supplementation is sufficient to rescue cancer-induced muscle wasting and function.
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Elisabeth wyart
PROVIDER: S-SCDT-EMBOR-2021-53746V1 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.
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Project description:Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein we identified the transcriptional repressor protein, Forkhead box P1 (FoxP1), as a downstream target gene of FoxO1 whose skeletal muscle expression is elevated in multiple models of cancer cachexia and in patients with cancer who exhibit cachexia. Through generation of inducible skeletal muscle-specific FoxP1 over-expressing (FoxP1iSkmTg/Tg) mice, we demonstrate that FoxP1 upregulation is sufficient to induce features of cachexia, including body and skeletal muscle wasting characterized by reduced muscle fiber cross-sectional area of type IIX/B muscle fibers. Muscles from FoxP1iSkmTg/Tg mice also showed significant muscle damage and myopathy characterized by the accumulation of p62 and cellular material-filled vesicles, the presence of centrally nucleated myofibers, and were significantly weaker than controls. In the context of cancer cachexia, blocking FoxP1 upregulation prevented the cancer-induced repression of target genes critical to muscle structural integrity and repair, including Myocyte enhancer factor 2c (Mef2c), improved muscle ultrastructure and significantly attenuated muscle fiber atrophy. We further show that the muscle wasting phenotype induced by FoxP1 required the activity of histone deacetylase (HDAC) proteins, which are well-established to cooperate with FoxP1 to mediate gene repression, and which were necessary for FoxP1-dependent repression of Mef2c. In summary, we identify FoxP1 as a negative transcriptional regulator of skeletal muscle mass and function, whose up-regulation mediates cancer-induced muscle wasting. We used microarrays to investigate the genome-wide transcriptional networks regulated by the FoxO1 and FoxP1 transcription factors in skeletal muscle of tumor-bearing mice.
2021-04-28 | GSE153068 | GEO
Project description:Cancer cachexia is a severe and disabling clinical condition that frequently accompanies the development of many types of cancer. Muscle wasting is the hallmark of cancer cachexia and is associated with serious clinical consequences such as physical impairment, poor quality of life, reduced tolerance to treatments and shorter survival. Cancer cachexia may evolve through different stages of clinical relevance, namely pre-cachexia, cachexia and refractory cachexia. Given its detrimental clinical consequences, it appears mandatory to prevent and/or delay the progression of cancer cachexia to its refractory stage by implementing the early recognition and treatment of the nutritional and metabolic alterations occurring during cancer. Research on the molecular mechanisms underlying muscle wasting during cancer cachexia has expanded in the last few years, allowing the identification of several potential therapeutic targets and the development of many promising drugs. Several of these agents have already reached the clinical evaluation, but it is becoming increasingly evident that a single therapy may not be completely successful in the treatment of cancer-related muscle wasting, given its multifactorial and complex pathogenesis. This suggests that early and structured multimodal interventions (including targeted nutritional supplementation, physical exercise and pharmacological interventions) are necessary to prevent and/or treat the devastating consequences of this cancer comorbidity, and future research should focus on this approach.
| S-EPMC5424865 | biostudies-literature
Project description:Cancer-associated cachexia, characterized by muscle wasting, is a lethal metabolic syndrome without defined etiology or established treatment. We previously found that p300 mediates cancer-induced muscle wasting by activating C/EBPβ, which then upregulates key catabolic genes. However, the signaling mechanism that activates p300 in response to cancer is unknown. Here, we show that upon cancer-induced activation of Toll-like receptor 4 in skeletal muscle, p38β MAPK phosphorylates Ser-12 on p300 to stimulate C/EBPβ acetylation, which is necessary and sufficient to cause muscle wasting. Thus, p38β MAPK is a central mediator and therapeutic target of cancer-induced muscle wasting. In addition, nilotinib, an FDA-approved kinase inhibitor that preferentially binds p38β MAPK, inhibited p300 activation 20-fold more potently than the p38α/β MAPK inhibitor, SB202190, and abrogated cancer cell-induced muscle protein loss in C2C12 myotubes without suppressing p38α MAPK-dependent myogenesis. Systemic administration of nilotinib at a low dose (0.5 mg/kg/day, i.p.) in tumor-bearing mice not only alleviated muscle wasting, but also prolonged survival. Therefore, nilotinib appears to be a promising treatment for human cancer cachexia due to its selective inhibition of p38β MAPK. SIGNIFICANCE: These findings demonstrate that prevention of p38β MAPK-mediated activation of p300 by the FDA-approved kinase inhibitor, nilotinib, ameliorates cancer cachexia, representing a potential therapeutic strategy against this syndrome.
| S-EPMC8456613 | biostudies-literature
Project description:Cachexia is a multifactorial syndrome characterized by muscle loss that cannot be reversed by conventional nutritional support. To uncover the molecular basis underlying the onset of cancer cachectic muscle wasting and establish an effective intervention against muscle loss, we used a cancer cachectic mouse model and examined the effects of aerobic exercise. Aerobic exercise successfully suppressed muscle atrophy and activated adiponectin signaling. Next, a cellular model for cancer cachectic muscle atrophy using C2C12 myotubes was prepared by treating myotubes with a conditioned medium from a culture of colon-26 cancer cells. Treatment of the atrophic myotubes with recombinant adiponectin was protective against the thinning of cells through the increased production of p-mTOR and suppression of LC3-II. Altogether, these findings suggest that the activation of adiponectin signaling could be part of the molecular mechanisms by which aerobic exercise ameliorates cancer cachexia-induced muscle wasting.
| S-EPMC8002946 | biostudies-literature
Project description:Purpose of reviewWe highlight evidence for sexual dimorphism in preclinical and clinical studies investigating the cause and treatment of cancer cachexia.Recent findingsCancer cachexia is unintended bodyweight loss occurring with cancer, and skeletal muscle wasting is a critical predictor of negative outcomes in the cancer patient. Skeletal muscle exhibits sexual dimorphism in fiber type, function, and regeneration capacity. Sex differences have been implicated in skeletal muscle metabolism, mitochondrial function, immune response to injury, and myogenic stem cell regulation. All of these processes have the potential to be involved in cancer-induced muscle wasting. Unfortunately, the vast majority of published studies examining cancer cachexia in preclinical models or cancer patients either have not accounted for sex in their design or have exclusively studied males. Preclinical studies have established that ovarian function and estradiol can affect skeletal muscle function, metabolism and mass; ovarian function has also been implicated in the sensitivity of circulating inflammatory cytokines and the progression of cachexia.SummaryFemales and males have unique characteristics that effect skeletal muscle's microenvironment and intrinsic signaling. These differences provide a strong rationale for distinct causes for cancer cachexia development and treatment in males and females.
| S-EPMC6239206 | biostudies-literature
Project description:Sepsis elicits skeletal muscle weakness and fiber atrophy. The accumulation of injured mitochondria and depressed mitochondrial functions are considered as important triggers of sepsis-induced muscle atrophy. It is unclear whether mitochondrial dysfunctions in septic muscles are due to the inadequate activation of quality control processes. We hypothesized that overexpressing Parkin, a protein responsible for the recycling of dysfunctional mitochondria by the autophagy pathway (mitophagy), would confer protection against sepsis-induced muscle atrophy by improving mitochondrial quality and content. Parkin was overexpressed for four weeks in the limb muscles of four-week old mice using intramuscular injections of adeno-associated viruses (AAVs). The cecal ligation and perforation (CLP) procedure was used to induce sepsis. Sham operated animals were used as controls. All animals were studied for 48 h post CLP. Sepsis resulted in major body weight loss and myofiber atrophy. Parkin overexpression prevented myofiber atrophy in CLP mice. Quantitative two-dimensional transmission electron microscopy revealed that sepsis is associated with the accumulation of enlarged and complex mitochondria, an effect which was attenuated by Parkin overexpression. Parkin overexpression also prevented a sepsis-induced decrease in the content of mitochondrial subunits of NADH dehydrogenase and cytochrome C oxidase. We conclude that Parkin overexpression prevents sepsis-induced skeletal muscle atrophy, likely by improving mitochondrial quality and contents.
| S-EPMC7349807 | biostudies-literature
Project description:Significance: Cancer is frequently associated with the early appearance of cachexia, a multifactorial wasting syndrome. If not present at diagnosis, cachexia develops either as a result of tumor progression or as a side effect of anticancer treatments, especially of standard chemotherapy, eventually representing the direct cause of death in up to one-third of all cancer patients. Cachexia, within its multiorgan affection, is characterized by severe loss of muscle mass and function, representing the most relevant subject of preclinical and clinical investigation. Recent Advances: The pathogenesis of muscle wasting in cancer- and chemotherapy-induced cachexia is complex, and encompasses heightened protein catabolism and reduced anabolism, disrupted mitochondria and energy metabolism, and even neuromuscular junction dismantling. The mechanisms underlying these alterations are still controversial, especially concerning the molecular drivers that could be targeted for anticachexia therapies. Inflammation and mitochondrial oxidative stress are among the principal candidates; the latter being extensively discussed in the present review. Critical Issues: Several approaches have been tested to modulate the redox homeostasis in tumor hosts, and to counteract cancer- and chemotherapy-induced muscle wasting, from exercise training to distinct classes of direct or indirect antioxidants. We herein report the most relevant results obtained from both preclinical and clinical trials. Future Directions: Including the assessment and the treatment of altered redox balance in the clinical management of cancer patients is still a big challenge. The available evidence suggests that fortifying the antioxidant defenses by either pharmacological or nonpharmacological strategies will likely improve cachexia and eventually the outcome of a broad cancer patient population. Antioxid. Redox Signal. 38, 352-370.
| S-EPMC10081727 | biostudies-literature
Project description:Existing data suggest that NF-kappaB signaling is a key regulator of cancer-induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-κB transcription factors that regulate wasting is far from complete. In muscles of C26 tumor bearing mice, overexpression of dominant negative (d.n.) IKKβ blocked muscle wasting by 69% and the IκBα-super repressor blocked wasting by 41%. In contrast, overexpression of d.n. IKKα or d.n. NIK did not block C26-induced wasting. Surprisingly, overexpression of d.n. p65 or d.n. c-Rel did not significantly affect muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-κB transcription factors, we compared genome-wide p65 binding to DNA in control and cachectic muscle using ChIP-sequencing. Bioinformatic analysis of ChIP-sequencing data from control and C26 muscles showed very little p65 binding to genes in cachexia and little to suggest that upregulated p65 binding influences the gene expression associated with muscle based cachexia. The p65 ChIP-seq data are consistent with our finding of no significant change in protein binding to an NF-κB oligonucleotide in a gel shift assay, no activation of a NF-κB-dependent reporter, and no effect of d.n.p65 overexpression in muscles of tumor bearing mice. Taken together, these data support the idea that although inhibition of IκBα, and particularly IKKβ, blocks cancer-induced wasting, the alternative NF-κB signaling pathway is not required. In addition, the downstream NF-κB transcription factors, p65 and c-Rel do not appear to regulate the transcriptional changes induced by the C26 tumor. These data are consistent with the growing body of literature showing that there are NF-κB-independent substrates of IKKβ and IκBα that regulate physiological processes.
| S-EPMC3906224 | biostudies-literature
Project description:Prostate cancer and its treatment may induce muscle wasting. Body composition and muscle functionality are rarely assessed in patients with prostate cancer from developing countries due to the limited availability of high-quality equipment for routine diagnosis. This cross-sectional study evaluated the association between several simplistic techniques for assessing muscle mass and function with a more complex standard of reference for muscle wasting among Mexican men with prostate cancer. Muscle wasting was highly prevalent, yet it was presumably associated with aging rather than cancer and its treatment itself. The restricted availability of specific equipment in clinical settings with technological limitations supports using unsophisticated techniques as surrogate measurements for muscle wasting. The left-arm handgrip dynamometry displayed the highest correlation with the standard of reference and exhibited an acceptable predicted probability for muscle estimation. Combining several simplistic techniques may be preferable. We also developed and internally validated a manageable model that helps to identify elderly patients with prostate cancer at risk of muscle depletion and impairment. These findings promote the early recognition and treatment of muscle wasting alterations occurring among older adults with prostate cancer.
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