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Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice
Pradyut K Paul1, Sanjay K Gupta, Shephali Bhatnagar
1Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Abstract:
Skeletal muscle wasting is a major human morbidity, and contributes to mortality in a variety of clinical settings, including denervation and cancer cachexia. In this study, we demonstrate that the expression level and autoubiquitination of tumor necrosis factor (α) receptor adaptor protein 6 (TRAF6), a protein involved in receptor-mediated activation of several signaling pathways, is enhanced in skeletal muscle during atrophy. Skeletal muscle-restricted depletion of TRAF6 rescues myofibril degradation and preserves muscle fiber size and strength upon denervation. TRAF6 mediates the activation of JNK1/2, p38 mitogen-activated protein kinase, adenosine monophosphate-activated protein kinase, and nuclear factor κB, and induces the expression of muscle-specific E3 ubiquitin ligases and autophagy-related molecules in skeletal muscle upon denervation. Inhibition of TRAF6 also preserves the orderly pattern of intermyofibrillar and subsarcolemmal mitochondria in denervated muscle. Moreover, depletion of TRAF6 prevents cancer cachexia in an experimental mouse model. This study unveils a novel mechanism of skeletal muscle atrophy and suggests that TRAF6 is an important therapeutic target to prevent skeletal muscle wasting.
Insights
Tumor necrosis factor receptor adaptor protein 6 (TRAF6) drives skeletal muscle wasting during denervation and cancer cachexia. Inhibiting TRAF6 preserves muscle mass and strength, identifying it as a key therapeutic target.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Skeletal muscle wasting (atrophy) is a significant cause of morbidity and mortality in various clinical conditions.
- The molecular mechanisms underlying muscle atrophy, particularly in response to denervation and cancer cachexia, require further elucidation.
Purpose of the Study:
- To investigate the role of tumor necrosis factor (α) receptor adaptor protein 6 (TRAF6) in skeletal muscle atrophy.
- To determine if TRAF6 is a potential therapeutic target for preventing muscle wasting.
Main Methods:
- Analyzing TRAF6 expression and autoubiquitination in atrophied skeletal muscle.
- Utilizing skeletal muscle-specific TRAF6 depletion in mouse models of denervation and cancer cachexia.
- Assessing the impact of TRAF6 inhibition on muscle fiber integrity, strength, and mitochondrial organization.
Main Results:
- TRAF6 expression and autoubiquitination are elevated in skeletal muscle during atrophy.
- Skeletal muscle-specific depletion of TRAF6 prevents myofibril degradation, preserves muscle fiber size and strength in denervated mice.
- TRAF6 inhibition mitigates cancer cachexia in a mouse model.
- TRAF6 activation of signaling pathways (JNK1/2, p38 MAPK, AMPK, NF-κB) and induction of E3 ubiquitin ligases contribute to muscle atrophy.
Conclusions:
- TRAF6 plays a critical role in mediating skeletal muscle wasting through the activation of specific signaling pathways and induction of catabolic processes.
- Targeting TRAF6 offers a promising therapeutic strategy to combat muscle atrophy in diverse clinical settings like denervation and cancer cachexia.
