Cancer Takes a Toll on Skeletal Muscle by Releasing Heat Shock Proteins—An Emerging Mechanism of Cancer-Induced Cachexia

Cancer-associated cachexia (cancer cachexia) is a major contributor to the modality and mortality of a wide variety of solid tumors. It is estimated that cachexia inflicts approximately ~60% of all cancer patients and is the immediate cause of ~30% of all cancer-related death. However, there is no established treatment of this disorder due to the poor understanding of its underlying etiology. The key manifestations of cancer cachexia are systemic inflammation and progressive loss of skeletal muscle mass and function (muscle wasting). A number of inflammatory cytokines and members of the TGFβ superfamily that promote muscle protein degradation have been implicated as mediators of muscle wasting. However, clinical trials targeting some of the identified mediators have not yielded satisfactory results. Thus, the root cause of the muscle wasting associated with cancer cachexia remains to be identified. This review focuses on recent progress of laboratory studies in the understanding of the molecular mechanisms of cancer cachexia that centers on the role of systemic activation of Toll-like receptor 4 (TLR4) by cancer-released Hsp70 and Hsp90 in the development and progression of muscle wasting, and the downstream signaling pathways that activate muscle protein degradation through the ubiquitin–proteasome and the autophagy–lysosome pathways in response to TLR4 activation. Verification of these findings in humans could lead to etiology-based therapies of cancer cachexia by targeting multiple steps in this signaling cascade.

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Electrical Stimulated Glut4 Signaling Attenuates Critical Illness-Associated Muscle Wasting

10.1101/2021.11.11.468054 ◽

2021 ◽

Author(s):

Alex Bernard Addinsall ◽

Nicola Cacciani ◽

Anders Backeus ◽

Yvette Hedstrom ◽

Lars Larsson

Keyword(s):

Critical Care ◽

Critical Illness ◽

Protein Degradation ◽

Soleus Muscle ◽

Muscle Wasting ◽

Muscle Protein ◽

Cross Sectional ◽

Controlled Mechanical Ventilation ◽

Muscle Protein Degradation ◽

And Function

Background: Critical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a byproduct of critical care, attributed to impaired recovery, longterm complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood, however loss of mechanical stimuli contributes to critical illness associated muscle atrophy and weakness. Passive mechanical loading (ML) and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care. Methods: Rats were subjected to 8 days critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and Western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM. Results: Following 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, Myosin:Actin ratio and single muscle fiber maximum force normalized to cross-sectional area (specific force) were reduced by 40-50% (p< 0.0001). ES significantly reduced the loss of soleus muscle fiber cross-sectional area (CSA) and Myosin:Actin ratio by approximately 30% (p< 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signaling in the soleus muscle following critical care and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (p< 0.01). ES promoted phosphofructokinase and insulin signaling pathways to control levels (p< 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signaling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (p= 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately 2-fold (p= 0.06). Reduction of muscle protein degradation rather than protein synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (p= 0.006) and MuRF1 (p= 0.08) by approximately 50%, downstream of AMPK-FoxO3. Conclusions: ES maintained GLUT4 translocation through increased AMPK-TBC1D4 signaling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signaling and reduced muscle protein degradation in CIM.

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Effects of An Omega‐3 High‐Fat Diet on Skeletal Muscle Protein Degradation in Glucocorticoid‐Induced Muscle Wasting

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.05729 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Melissa Puppa ◽

Katie Brown ◽

Aaron Persinger

Keyword(s):

Skeletal Muscle ◽

Protein Degradation ◽

High Fat Diet ◽

Muscle Wasting ◽

Muscle Protein ◽

Omega 3 ◽

Skeletal Muscle Protein ◽

High Fat ◽

Muscle Protein Degradation

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The Biological Mechanisms of Cancer-Related Skeletal Muscle Wasting: The Role of Progressive Resistance Exercise

Biological Research For Nursing ◽

10.1177/1099800408317345 ◽

2008 ◽

Vol 10 (1) ◽

pp. 7-20 ◽

Cited By ~ 54

Author(s):

Sadeeka Al-Majid ◽

Haidee Waters

Keyword(s):

Skeletal Muscle ◽

Resistance Exercise ◽

Protein Degradation ◽

Proinflammatory Cytokines ◽

Muscle Wasting ◽

Muscle Protein ◽

Skeletal Muscle Protein ◽

Skeletal Muscle Wasting ◽

Muscle Protein Degradation ◽

Progressive Resistance Exercise

Cancer results in perturbations in skeletal muscle protein metabolism leading to muscle wasting. Although severe wasting is seen primarily in persons with advanced malignancies, a number of cancer patients show some degree of wasting at presentation. Although cancer-related skeletal muscle wasting is attributable, in part, to decreased muscle protein synthesis, its primary cause appears to be increased muscle protein degradation. Although several proteolytic systems may be involved, compelling evidence suggests that the major system responsible for skeletal muscle protein degradation in cancer is the ATP-dependent ubiquitin— proteasome system. Other contributing factors include proinflammatory cytokines and the tumor-released proteolysis-inducing factor. Decreased physical activity and decreased nutritional intake may also play a role. Cancer-related skeletal muscle wasting is clinically significant because of its profound effects on functional outcomes and quality of life. Nevertheless, no specific interventions have proved to be effective in preventing or reversing the problem. Interventions such as nutritional supplementation and appetite stimulants are only partially helpful. A nonpharmacologic intervention that may attenuate cancer-related skeletal muscle wasting is progressive resistance exercise training (PRT). PRT is a potent stimulus of growth in muscle mass and strength. PRT may attenuate cancer-related skeletal muscle wasting by downregulating the activity of proinflammatory cytokines and by increasing the phosphorylation of intramuscular amino acid—signaling molecules. This article discusses several cancer-related skeletal muscle wasting mechanisms and proposes how PRT might attenuate muscle wasting by counteracting some of these mechanisms.

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