Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin/+ mouse

Manne, Nandini D.P.K.; Lima, Maria; Enos, Reilly T.; Wehner, Paulette; Carson, James A.; Blough, Eric R.

doi:10.3892/ijo.2013.1893

Cited by 50 publications

(57 citation statements)

References 30 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with the increased AMPK phosphorylation, markers of autophagy including LC3-II, cathepsin L, and beclin were elevated in cachectic hearts from tumorbearing rodents, and electron microscopy has revealed the presence of double-membraned autophagic vacuoles containing portions of cytoplasm, mitochondria, and myelin-like structures (25,67,101).…”

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 66%

“…Interestingly, the reductions in mTOR/S6/4E-BP1 in this study occurred in the face of elevated Akt (protein kinase B) phosphorylation (67), but studies have found that IL-6-mediated suppression of this pathway is independent of Akt (90). Cachectic hearts from Apc Min/ϩ mice also exhibited increased phosphorylation of 5=-adenosine monophosphate-activated protein kinase (AMPK), which can lead to autophagy and inhibition of mTOR, and is suggestive of increased signaling of degradative pathways (67). However, phosphorylation of Bad (Ser136), which reduces Bad-mediated apoptosis and cell death was increased in Apc Min/ϩ hearts (67).…”

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 96%

“…Min/ϩ mouse model of cancer cachexia (67). Interestingly, the reductions in mTOR/S6/4E-BP1 in this study occurred in the face of elevated Akt (protein kinase B) phosphorylation (67), but studies have found that IL-6-mediated suppression of this pathway is independent of Akt (90).…”

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 98%

“…Cachectic hearts from Apc Min/ϩ mice also exhibited increased phosphorylation of 5=-adenosine monophosphate-activated protein kinase (AMPK), which can lead to autophagy and inhibition of mTOR, and is suggestive of increased signaling of degradative pathways (67). However, phosphorylation of Bad (Ser136), which reduces Bad-mediated apoptosis and cell death was increased in Apc Min/ϩ hearts (67). Taken together, with the fact that despite the large decrease in protein synthesis rate, cardiac mass in Apc Min/ϩ mice was only reduced by 6 -8%, these findings suggest that protein degradation may actually be decreased rather than increased in cachectic hearts from Apc Min/ϩ mice, but direct measurement of protein degradation rates are required to confirm this hypothesis.…”

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 99%

See 3 more Smart Citations

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

Murphy

2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia.

show abstract

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 66%

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 96%

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 98%

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Protein mentioning

confidence: 99%

See 2 more Smart Citations

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

Murphy

2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Autophagy is a highly conserved lysosome‐driven degradation pathway of cellular constituents, normally activated at basal level to maintain cell homeostasis. Emerging data clearly show that induction of autophagy occurs in the skeletal muscle and in the heart in different experimental models of cancer cachexia and that it strongly contributes to the pathogenesis of muscle wasting . Whether autophagy is also modulated in cachectic patient is subject to debate.…”

Section: Introductionmentioning

confidence: 99%

Megestrol acetate improves cardiac function in a model of cancer cachexia‐induced cardiomyopathy by autophagic modulation

Musolino

Palus

Tschirner

et al. 2016

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

BackgroundCachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti‐cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant megestrol acetate (MA) has been discussed as a treatment for cachexia.MethodsIn this study the effects of MA were tested in cachectic tumour‐bearing rats (Yoshida AH‐130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis.ResultsTreatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (−9 ± 12%, P < 0.05) and the wasting of lean and fat mass (−7.0 ± 6% and −22.4 ± 3 %, P < 0.001 and P < 0.05, respectively). Administration of 100 mg/kg/day MA significantly protected the heart from general atrophy (633.8 ± 30 mg vs. placebo 474 ± 13 mg, P < 0.001). Tumour‐bearing rats displayed cardiac dysfunction, as indicated by the significant impairment of the left ventricular ejection fraction, the left ventricular fractional shortening, the stroke volume, the end dyastolic volume, and the end systolic volume. In contrast, MA significantly improved left ventricular ejection fraction, left ventricular fractional shortening, and left ventricular end systolic volume. Western blotting analysis showed an upregulation of the autophagic pathway in the gastrocnemius and hearts of the placebo‐treated tumour‐bearing rats. Treatment with MA, however, was able to modulate the autophagic markers (e.g. Beclin‐1, p62, TRAF6, and LC3) in the gastrocnemius and in the hearts of tumour‐bearing rats. Most importantly, 100 mg/kg/day MA reduced mortality [hazard ratio (HR): 0.44; 95%CI: 0.20–1.00; P = 0.0486].ConclusionsMegestrol acetate improved survival and reduced wasting through a marked downregulation of autophagy, occurring in both skeletal and heart muscle, the latter effect leading to a significant improvement of cardiac function. Our data suggest that MA might represent a valuable strategy to counteract the development of cancer cachexia‐induced cardiomyopathy.

show abstract

The pathophysiology of cancer‐mediated cardiac cachexia and novel treatment strategies: A narrative review

Tichy,

Parry

2023

Cancer Medicine

View full text Add to dashboard Cite

SignificanceTwo of the leading causes of death worldwide are cancer and cardiovascular diseases. Most cancer patients suffer from a metabolic wasting syndrome known as cancer‐induced cardiac cachexia, resulting in death in up to 30% of cancer patients. Main symptoms of this disease are severe cardiac muscle wasting, cardiac remodeling, and cardiac dysfunction. Metabolic alterations, increased inflammation, and imbalance of protein homeostasis contribute to the progression of this multifactorial syndrome, ultimately resulting in heart failure and death. Cancer‐induced cardiac cachexia is associated with decreased quality of life, increased fatiguability, and decreased tolerance to therapeutic interventions.Recent advancesWhile molecular mechanisms of this disease are not fully understood, researchers have identified different stages of progression of this disease, as well as potential biomarkers to detect and monitor the development. Preclinical and clinical studies have shown positive results when implementing certain pharmacological and non‐pharmacological therapy interventions.Critical issuesThere are still no clear diagnostic criteria for cancer‐mediated cardiac cachexia and the condition remains untreated, leaving cancer patients with irreversible effects of this syndrome. While traditional cardiovascular therapy interventions, such as beta‐blockers, have shown some positive results in preclinical and clinical research studies, recent preclinical studies have shown more successful results with certain non‐traditional treatment options that have not been further evaluated yet. There is still no clinical standard of care or approved FDA drug to aid in the prevention or treatment of cancer‐induced cardiac cachexia. This review aims to revisit the still not fully understood pathophysiological mechanisms of cancer‐induced cardiac cachexia and explore recent studies using novel treatment strategies.Future directionsWhile research has progressed, further investigations might provide novel diagnostic techniques, potential biomarkers to monitor the progression of the disease, as well as viable pharmacological and non‐pharmacological treatment options to increase quality of life and reduce cancer‐induced cardiac cachexia‐related mortality.

show abstract

Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin/+ mouse

Cited by 50 publications

References 30 publications

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

Megestrol acetate improves cardiac function in a model of cancer cachexia‐induced cardiomyopathy by autophagic modulation

The pathophysiology of cancer‐mediated cardiac cachexia and novel treatment strategies: A narrative review

Contact Info

Product

Resources

About