Aerobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2α Modulation

Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-α. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2α activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia.

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Functional adaptations of rat skeletal muscle arterioles to aerobic exercise training

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.6.2052 ◽

1992 ◽

Vol 72 (6) ◽

pp. 2052-2062 ◽

Cited By ~ 68

Author(s):

J. M. Lash ◽

H. G. Bohlen

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Aerobic Exercise ◽

Citrate Synthase ◽

Treadmill Exercise ◽

Oxidative Capacity ◽

Aerobic Exercise Training ◽

Vascular Density ◽

Muscle Tissues

This study tested the hypothesis that both structural and functional adaptations of arterioles occur within the skeletal muscle of rats aerobically trained for 8–10 wk with treadmill exercise. The training regimen used has been shown to elicit a 37% increase in plantaris citrate synthase activity but did not result in an elevation in citrate synthase activity in the spinotrapezius or gracilis muscles of rats used in this study. In the in vivo resting spinotrapezius muscle, arteriole diameters were similar in sedentary (SED) and trained (TR) rats. However, large- (1A) and intermediate- (2A) sized arterioles dilated proportionately more in TR than in SED rats during 1- to 8-Hz muscle contractions, even though the passive mechanical properties (circumference-passive wall tension relationships) were similar between groups. Vascular casts demonstrated a trend for an increase in the number of small (3A) arterioles and an approximately 20% increase in the passive diameter of 1A and 2A arterioles in the spinotrapezius muscle of TR rats. In contrast, in the gracilis muscle, arteriole diameters and density were identical in SED and TR rats, but the capillary-to-muscle fiber ratio was approximately 15% higher in TR rats. The results suggest that aerobic exercise training can greatly increase functional vasodilation and induce a slight increase in vascular density in skeletal muscle tissues, even if the oxidative capacity of these tissues is not increased by the training regimen.

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The impact of statin therapy and aerobic exercise training on skeletal muscle and whole-body aerobic capacity

American Heart Journal Plus: Cardiology Research and Practice ◽

10.1016/j.ahjo.2021.100028 ◽

2021 ◽

pp. 100028

Author(s):

Jill M. Slade ◽

George S. Abela ◽

Mitchell Rozman ◽

Robert J. McClowry ◽

David Hurley ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Aerobic Exercise ◽

Statin Therapy ◽

Aerobic Capacity ◽

Aerobic Exercise Training ◽

Whole Body ◽

The Impact

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Impact of Sarcopenia as a Prognostic Biomarker of Bladder Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms19102999 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2999 ◽

Cited By ~ 18

Author(s):

Hiroshi Fukushima ◽

Kosuke Takemura ◽

Hiroaki Suzuki ◽

Fumitaka Koga

Keyword(s):

Skeletal Muscle ◽

Bladder Cancer ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Cancer Cachexia ◽

Prognostic Biomarker ◽

Inflammatory Diseases ◽

Patients With Cancer ◽

Poor Nutritional Status ◽

The Impact

Sarcopenia, the degenerative and systemic loss of skeletal muscle mass, indicates patient frailty and impaired physical function. Sarcopenia can be caused by multiple factors, including advanced age, lack of exercise, poor nutritional status, inflammatory diseases, endocrine diseases, and malignancies. In patients with cancer cachexia, anorexia, poor nutrition and systemic inflammation make the metabolic state more catabolic, resulting in sarcopenia. Thus, sarcopenia is considered as one of manifestations of cancer cachexia. Recently, growing evidence has indicated the importance of sarcopenia in the management of patients with various cancers. Sarcopenia is associated with not only higher rates of treatment-related complications but also worse prognosis in cancer-bearing patients. In this article, we summarized metabolic backgrounds of cancer cachexia and sarcopenia and definitions of sarcopenia based on computed tomography (CT) images. We conducted a systematic literature review regarding the significance of sarcopenia as a prognostic biomarker of bladder cancer. We also reviewed recent studies focusing on the prognostic role of changes in skeletal muscle mass during the course of treatment in bladder cancer patients. Lastly, we discussed the impact of nutritional support, medication, and exercise on sarcopenia in cancer-bearing patients.

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Low-intensity aerobic exercise training: inhibition of skeletal muscle atrophy in high-fat-diet-induced ovariectomized rats

The Journal of Exercise Nutrition and Biochemistry ◽

10.20463/jenb.2017.0022 ◽

2017 ◽

Vol 21 (3) ◽

pp. 19-25 ◽

Cited By ~ 8

Author(s):

Hye Jin Kim ◽

Won Jun Lee

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Aerobic Exercise ◽

Muscle Atrophy ◽

High Fat Diet ◽

Aerobic Exercise Training ◽

Ovariectomized Rats ◽

Skeletal Muscle Atrophy ◽

High Fat ◽

Low Intensity

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Effects of aerobic exercise training on the protein kinase B (PKB)/mammalian target of rapamycin (mTOR) signaling pathway in aged skeletal muscle

Experimental Gerontology ◽

10.1016/j.exger.2003.12.005 ◽

2004 ◽

Vol 39 (3) ◽

pp. 379-385 ◽

Cited By ~ 13

Author(s):

Thomas H Reynolds ◽

Pamela Reid ◽

Lisa M Larkin ◽

Donald R Dengel

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Exercise Training ◽

Aerobic Exercise ◽

Signaling Pathway ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Aerobic Exercise Training ◽

Mtor Signaling Pathway

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Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.1.r133 ◽

2001 ◽

Vol 281 (1) ◽

pp. R133-R139 ◽

Cited By ~ 20

Author(s):

S. E. Samuels ◽

A. L. Knowles ◽

T. Tilignac ◽

E. Debiton ◽

J. C. Madelmont ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Cancer Cachexia ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Human Condition ◽

Skeletal Muscle Protein ◽

Tumor Bearing

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

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