scholarly journals Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 597 ◽  
Author(s):  
Vanina Romanello ◽  
Marco Scalabrin ◽  
Mattia Albiero ◽  
Bert Blaauw ◽  
Luca Scorrano ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Premature Death ◽  
Muscle Loss ◽  
Mitochondrial Network ◽  
Double Knockout ◽  
Physiological Relevance ◽  
Simultaneous Inhibition

The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors.

scholarly journals Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2536
Author(s):  
Giorgio Aquila ◽  
Andrea David Re Cecconi ◽  
Jeffrey J. Brault ◽  
Oscar Corli ◽  
Rosanna Piccirillo
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Premature Death ◽  
Preclinical Studies ◽  
Current State ◽  
Causal Therapy ◽  
And Oxidative Stress

Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our understanding of the mechanisms contributing to muscle wasting during cancer has markedly increased. Both inflammation and oxidative stress (OS) alter anabolic and catabolic signaling pathways mostly culminating with muscle depletion. Several preclinical studies have emphasized the beneficial roles of several classes of nutraceuticals and modes of physical exercise, but their efficacy in CC patients remains scant. The route of nutraceutical administration is critical to increase its bioavailability and achieve the desired anti-cachexia effects. Accumulating evidence suggests that a single therapy may not be enough, and a bimodal intervention (nutraceuticals plus exercise) may be a more effective treatment for CC. This review focuses on the current state of the field on the role of inflammation and OS in the pathogenesis of muscle atrophy during CC, and how nutraceuticals and physical activity may act synergistically to limit muscle wasting and dysfunction.

scholarly journals Impact of Cancer Cachexia on Cardiac and Skeletal Muscle: Role of Exercise Training

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 342
Author(s):  
Cláudia Bordignon ◽  
Bethânia S. dos Santos ◽  
Daniela D. Rosa
Keyword(s):  
Cardiac Remodeling ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Clinical Evidence ◽  
Premature Death ◽  
Muscle Loss ◽  
Multimodal Approach ◽  
Progressive Loss

Cachexia is a multifactorial syndrome that presents with, among other characteristics, progressive loss of muscle mass and anti-cardiac remodeling effect that may lead to heart failure. This condition affects about 80% of patients with advanced cancer and contributes to worsening patients’ tolerance to anticancer treatments and to their premature death. Its pathogenesis involves an imbalance in metabolic homeostasis, with increased catabolism and inflammatory cytokines levels, leading to proteolysis and lipolysis, with insufficient food intake. A multimodal approach is indicated for patients with cachexia, with the aim of reducing the speed of muscle wasting and improving their quality of life, which may include nutritional, physical, pharmacologic, and psychological support. This review aims to outline the mechanisms of muscle loss, as well as to evaluate the current clinical evidence of the use of physical exercise in patients with cachexia.

scholarly journals Muscle alterations in the development and progression of cancer-induced muscle atrophy: a review

2020 ◽  
Vol 128 (1) ◽  
pp. 25-41 ◽  
Author(s):  
Megan E. Rosa-Caldwell ◽  
Dennis K. Fix ◽  
Tyrone A. Washington ◽  
Nicholas P. Greene
Keyword(s):  
Cancer Patients ◽  
Protein Turnover ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Cell Function ◽  
Developmental Stages ◽  
Muscle Loss ◽  
Inflammatory Signaling ◽  
Mortality And Morbidity ◽  
Cancer Types

Cancer cachexia—cancer-associated body weight and muscle loss—is a significant predictor of mortality and morbidity in cancer patients across a variety of cancer types. However, despite the negative prognosis associated with cachexia onset, there are no clinical therapies approved to treat or prevent cachexia. This lack of treatment may be partially due to the relative dearth of literature on mechanisms occurring within the muscle before the onset of muscle wasting. Therefore, the purpose of this review is to compile the current scientific literature on mechanisms contributing to the development and progression of cancer cachexia, including protein turnover, inflammatory signaling, and mitochondrial dysfunction. We define “development” as changes in cell function occurring before the onset of cachexia and “progression” as alterations to cell function that coincide with the exacerbation of muscle wasting. Overall, the current literature suggests that multiple aspects of cellular function, such as protein turnover, inflammatory signaling, and mitochondrial quality, are altered before the onset of muscle loss during cancer cachexia and clearly highlights the need to study more thoroughly the developmental stages of cachexia. The studying of these early aberrations will allow for the development of effective therapeutics to prevent the onset of cachexia and improve health outcomes in cancer patients.

scholarly journals TAT-μUtrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice

2011 ◽  
Vol 111 (1) ◽  
pp. 200-205 ◽  
Author(s):  
Jarrod A. Call ◽  
James M. Ervasti ◽  
Dawn A. Lowe
Keyword(s):  
Knockout Mice ◽  
Skeletal Muscles ◽  
Ex Vivo ◽  
Eccentric Contraction ◽  
Mdx Mice ◽  
Double Knockout ◽  
Replacement Treatment ◽  
Generating Capacity

Previously, we demonstrated functional substitution of dystrophin by TAT-μUtrophin (TAT-μUtr) in dystrophin-deficient mdx mice. Herein, we addressed whether TAT-μUtr could improve the phenotype of dystrophin and utrophin double-knockout ( mdx:utr−/−) mice. Specifically, we quantitatively compared survival and quality of life assessments in mdx:utr−/− mice receiving TAT-μUtr protein administration against placebo-treated mdx:utr−/− mice (PBS). Additionally, skeletal muscles from TAT-μUtr and PBS mice were tested in vivo and ex vivo for strength and susceptibility to eccentric contraction-induced injury. We found the TAT-μUtr treatment extended life span 45% compared with mice administered PBS. This was attributed to significantly increased food consumption (3.1 vs. 1.8 g/24 h) due to improved ability to search for food as daily cage activities were greater in TAT-μUtr mice (e.g., 364 vs. 201 m ambulation/24 h). The extensor digitorum longus muscles of TAT-μUtr-treated double-knockout mice also displayed increased force-generating capacity ex vivo (8.3 vs. 6.4 N/cm2) and decreased susceptibility to injury ex vivo and in vivo. These data indicate that the functional benefits of TAT-μUtr replacement treatment extend to the mdx:utr−/− double-knockout mouse and support its development as a therapy to mitigate muscle weakness in patients with Duchenne muscular dystrophy.

scholarly journals Myostatin is a novel tumoral factor that induces cancer cachexia

2012 ◽  
Vol 446 (1) ◽  
pp. 23-36 ◽  
Author(s):  
Sudarsanareddy Lokireddy ◽  
Isuru Wijerupage Wijesoma ◽  
Sabeera Bonala ◽  
Meng Wei ◽  
Siu Kwan Sze ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Transforming Growth Factor ◽  
C2c12 Myotubes ◽  
E3 Ligases ◽  
Molecular Features ◽  
Skeletal Muscle Wasting

Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice.

scholarly journals Transduction of Full-length Dystrophin to Multiple Skeletal Muscles Improves Motor Performance and Life Span in Utrophin/Dystrophin Double Knockout Mice

2008 ◽  
Vol 16 (5) ◽  
pp. 825-831 ◽  
Author(s):  
Ryoko Kawano ◽  
Masatoshi Ishizaki ◽  
Yasushi Maeda ◽  
Yuji Uchida ◽  
En Kimura ◽  
...  
Keyword(s):  
Life Span ◽  
Knockout Mice ◽  
Motor Performance ◽  
Skeletal Muscles ◽  
Full Length ◽  
Double Knockout

scholarly journals p50–NF-κB Complexes Partially Compensate for the Absence of RelB: Severely Increased Pathology in p50−/−relB−/−Double-knockout Mice

1997 ◽  
Vol 185 (7) ◽  
pp. 1359-1370 ◽  
Author(s):  
Falk Weih ◽  
Stephen K. Durham ◽  
Debra S. Barton ◽  
William C. Sha ◽  
David Baltimore ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Double Mutant ◽  
Family Members ◽  
Premature Death ◽  
Mutant Mice ◽  
Mrna Levels ◽  
Double Knockout ◽  
Inflammatory Phenotype ◽  
Inflammatory Infiltrates ◽  
Disease Free

RelB-deficient mice (relB−/−) have a complex phenotype including multiorgan inflammation and hematopoietic abnormalities. To examine whether other NF-κB/Rel family members are required for the development of this phenotype or have a compensatory role, we have initiated a program to generate double-mutant mice that are deficient in more than one family member. Here we report the phenotypic changes in relB−/− mice that also lack the p50 subunit of NFκB (p50−/−). The inflammatory phenotype of p50−/−relB−/− double-mutant mice was markedly increased in both severity and extent of organ involvement, leading to premature death within three to four weeks after birth. Double-knockout mice also had strongly increased myeloid hyperplasia and thymic atrophy. Moreover, B cell development was impaired and, in contrast to relB−/− single knockouts, B cells were absent from inflammatory infiltrates. Both p50−/− and heterozygous relB−/+ animals are disease-free. In the absence of the p50, however, relB−/+ mice (p50−/−relB−/+) had a mild inflammatory phenotype and moderate myeloid hyperplasia. Neither elevated mRNA levels of other family members, nor increased κB-binding activities of NF-κB/Rel complexes could be detected in single- or double-mutant mice compared to control animals. These results indicate that the lack of RelB is, in part, compensated by other p50-containing complexes and that the “classical” p50-RelA–NF-κB activity is not required for the development of the inflammatory phenotype.

scholarly journals Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia

2016 ◽  
Vol 311 (1) ◽  
pp. C101-C115 ◽  
Author(s):  
Rulin Sun ◽  
Santao Zhang ◽  
Wenjun Hu ◽  
Xing Lu ◽  
Ning Lou ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Valproic Acid ◽  
Conditioned Medium ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Biological Effects ◽  
C2c12 Myotubes ◽  
Cross Sectional ◽  
Cell Conditioned Medium

Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia.

scholarly journals MMP12 Knockout Prevent Weight and Muscle Loss Induced by Cancer Cachexia

2021 ◽  
Author(s):  
Lingbi Jiang ◽  
Mingming Yang ◽  
Shihui He ◽  
Zhengyang Li ◽  
Haobin Li ◽  
...  
Keyword(s):  
Weight Loss ◽  
Interleukin 6 ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Critical Role ◽  
Muscle Loss ◽  
Glycolipid Metabolism ◽  
Patients With Cancer

AbstractWeight loss and muscle wasting can have devastating impacts on survival and quality of life of patients with cancer cachexia. Here, we have established a hybrid mouse of ApcMin/+ mice and MMP12 knockout mice (ApcMin/+; MMP12-/-) and found that knockout MMP12 can suppress the weight and muscle loss of ApcMin/+ mice. In detail, we found that interleukin 6 was highly upregulated in the serum of cancer patients and MMP12 was increased in muscle of tumor-bearing mice. Interestingly, the interleukin 6 secreted by tumor cells led to MMP12 overexpression in the macrophages, which further resulted in degradation of insulin and insulin-like growth factor 1 and interruption of glycolipid metabolism. Notably, depletion of MMP12 prevented weight loss of ApcMin/+ mice. Our study uncovers the critical role of MMP12 in controlling weight and highlights the great potential of MMP12 in the treatment of cancer cachexia.

scholarly journals RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality

2015 ◽  
Vol 112 (35) ◽  
pp. 11007-11012 ◽  
Author(s):  
Lingjun Meng ◽  
Wei Jin ◽  
Xiaodong Wang
Keyword(s):  
Knockout Mice ◽  
Premature Death ◽  
Skin Lesions ◽  
Atherosclerotic Plaques ◽  
Double Knockout ◽  
Interacting Protein ◽  
Course Of Disease ◽  
Inflammatory Monocytes ◽  
Apoe Knockout Mice ◽  
Single Knockout

Systematic inflammation contributes to the development of many diseases, including cardiovascular disease, which is the leading cause of mortality worldwide. How such inflammation is initiated and maintained throughout the course of disease remains unclear. In the current study, we report the observation of specific phosphorylation of the receptor-interacting protein 3 (RIP3) kinase that marks the activation of programmed necrosis (also called the “necroptosis pathway”) in the atherosclerotic plaques in apolipoprotein E (ApoE)-knockout mice. The mRNA expression levels of 10 inflammatory cytokines, including IL-1α, were decreased significantly in the plaque regions of mice lacking RIP3. Lymphocyte infiltrations in the adipocyte tissue and in skin lesions of ApoE single-knockout mice were significantly mitigated in ApoE/RIP3 double-knockout mice. The high percentage of inflammatory monocytes with high levels of lymphocyte antigen 6C in the blood of ApoE single-knockout mice also was greatly decreased in the ApoE/RIP3 double-knockout mice. Most significantly, the double-knockout mice displayed dramatically delayed mortality compared with ApoE single-knockout mice. Our findings indicate that necrotic death in areas such as atherosclerotic plaques may release cytokines that mobilize monocytes from bone marrow to the lesion sites, exacerbating the lesions in multiple tissues and resulting in the premature death of the animals.

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