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Withaferin A Attenuates Muscle Cachexia Induced by Angiotensin II Through Regulating Pathways Activated by
Sham S Kakar1,2, Vasa Vemuri1, Mariusz Z Ratajczak2,3
1Department of Physiology, University of Louisville, Louisville, KY 40202, USA.
Abstract:
Cachexia is a multifactorial syndrome characterized by severe muscle wasting and is a debilitating condition frequently associated with cancer. Previous studies from our group revealed that withaferin A (WFA), a steroidal lactone, mitigated muscle cachexia induced by ovarian tumors in NSG mice. However, it remains unclear whether WFA's protective effects are direct or secondary to its antitumor properties. We developed a cachectic model through continuous angiotensin II (Ang II) infusion in C57BL/6 mice to address this issue. Ang II infusion resulted in profound muscle atrophy, evidenced by significant reductions in grip strength and in the TA, GA, and GF muscle mass. Molecular analyses indicated elevated expression of inflammatory cytokines (TNFα, IL-6, MIP-2, IL-18, IL-1β), NLRP3 inflammasome, and genes associated with the UPS (MuRF1, MAFBx) and autophagy pathways (Bacl1, LC3B), along with suppression of anti-inflammatory heme oxygenase-1 (HO-1) and myogenic regulators (Pax7, Myod1). Strikingly, WFA treatment reversed these pathological changes, restoring muscle mass, strength, and molecular markers to near-normal levels. These findings demonstrate that WFA exerts direct anti-cachectic effects by targeting key inflammatory and atrophic pathways in skeletal muscle, highlighting its potential as a novel therapeutic agent for cachexia management.
Insights
Withaferin A (WFA) directly combats muscle wasting in cachexia by targeting inflammatory and atrophic pathways. This study shows WFA
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Cachexia is a severe muscle-wasting syndrome often linked to cancer.
- Withaferin A (WFA) previously showed potential in mitigating cancer-induced cachexia.
- The direct effects of WFA on muscle atrophy were not fully understood.
Purpose of the Study:
- To investigate the direct anti-cachectic effects of Withaferin A (WFA).
- To determine if WFA's protective effects are independent of its antitumor properties.
- To elucidate the molecular mechanisms underlying WFA's action on skeletal muscle.
Main Methods:
- A mouse model of cachexia was established using continuous angiotensin II (Ang II) infusion.
- Muscle mass, grip strength, and molecular markers of inflammation and atrophy were assessed.
- Key pathways including the ubiquitin-proteasome system (UPS) and autophagy were analyzed.
Main Results:
- Ang II infusion induced significant muscle atrophy, reduced strength, and altered molecular markers.
- WFA treatment reversed these effects, restoring muscle mass and function.
- WFA normalized the expression of inflammatory cytokines, UPS, and autophagy-related genes.
Conclusions:
- Withaferin A (WFA) demonstrates direct anti-cachectic effects on skeletal muscle.
- WFA targets key inflammatory and atrophic pathways, including the NLRP3 inflammasome, UPS, and autophagy.
- WFA shows potential as a therapeutic agent for managing muscle wasting in cachexia.
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