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Key Points
- AKG increased lean mass ratio by ~16.6%
- Restored running endurance, maximal running speed, grip strength, and cold tolerance
- Enhanced growth signals and reduced muscle-breakdown signals
- AKG reduced oxidative damage and inflammation linked to muscle aging
Methods
Thirty-six male mice (8 weeks old) were assigned to three groups. D-galactose was used to induce oxidative stress and inflammation to mimic aspects of aging.
- Control Group: saline for 8 weeks
- D-gal Model Group: 500 mg/kg/day D-galactose for 8 weeks
- D-gal + AKG Group: 500 mg/kg/day D-galactose + 1 mg/kg/day AKG for 8 weeks
Muscle Mass and Performance Restored
AKG reversed D-gal model body weight declines, increasing body weight and raising lean mass ratio.
"After 8 weeks of injection, the body weight of mice in the model group decreasedβ¦ AKG treatment resulted in a 7.3% increase in body weight in D-gal-induced aging mice compared to the model groupβ¦"
"...AKG treatment significantly increased the lean ratio of D-gal-induced aging mice by 16.6%"
Hindlimb muscle size followed the same pattern which AKG brought back to control-like levels.
"Ratios of TA and GAS in the model group were decreased by 18.2% and 16.1%. AKG intervention restored the ratios of TA and GAS in the model group to the levels of the control group."
Physical performance also declined in the aging model, with reductions in running endurance, maximal running speed, and grip strength. AKG restored all three measures.
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D-gal impaired:
- Running time (β18.4%)
- Max running speed (β12.8%)
- Grip strength (β24.5%)
"AKG intervention restored these parameters in the model group to control group levels."
The ability of skeletal muscles to maintain body temperature, a function reduced in the aging model, improved as well.
"These results indicated that the sarcopenia model was successfully established and AKG intervention could improve skeletal muscle mass and function in D-gal-induced sarcopenia."
Improved Muscle Structure and Protein Expression
Aging weakened the structural integrity of the muscle fibers, but these deficits were reversed with AKG.
"AKG treatment restored the cross-sectional area of muscle fibers in the model group to levels comparable to the control group."
Ultrastructural imaging showed that the aging model disrupted muscle fiber organization, while AKG restored normal patterns.
"The muscle fiber ultrastructure⦠was significantly restored, with near-complete integrity of the sarcomeres and a clear structure of I bands, A bands, Z lines, and M lines, resembling the organization of the control group."
Gene expression for major structural proteins, including actin, tropomyosin, troponin subunits, and multiple myosin heavy chains, declined in the aging mice. AKG increased their expression. Understanding why maintaining lean mass is crucial for healthspan provides important context for how interventions like AKG that preserve muscle structure and function can support healthy aging and metabolic resilience.
"Compared to the control group, the mRNA expressions [of structural genes] were significantly reduced to varying degrees in the model group. AKG treatment was able to increase the mRNA expressions of these proteins to varying degrees."
These improvements suggest AKG helps maintain better contractile capacity and muscle strength.
Protein Homeostasis Toward Synthesis
In the aging model mice, the pathways that support protein synthesis were weakened, while the pathways that promote muscle breakdown were overactive.
AKG boosted AKT/mTOR-driven synthesis while lowering the atrophy-related genes MAFbx and MuRF1.
"AKG intervention significantly alleviated the suppression of the protein synthesis pathway in the skeletal muscles."
"AKG intervention significantly downregulated the expression of these two proteins [MAFbx and MuRF1] to normal level, indicating that AKG treatment can inhibit the degradation of myofiber proteins."
These changes reflect a healthier protein-balance environment; more synthesis, less breakdown.
Mitochondrial Health & Oxidative Stress Improved
The aging model caused structural damage to mitochondria, which AKG alleviated.
"AKG treatment significantly alleviated the mitochondrial ultrastructure damage in the myofibers."
Oxidative stress markers were elevated in the aging mice. AKG significantly reduced them:
"Serum levels of ROS and malondialdehyde (MDA)... increased⦠while AKG treatment reduced 29.21% and 38.46%."
Superoxide dismutase (SOD), a key antioxidant for scavenging free radicals, increased significantly.
"AKG intervention increased the SOD activity in model mice by 4.6 times."
Inflammatory cytokines were also lowered with AKG treatment.
"AKG notably reduced the secretion of TNF-Ξ± and IL-6 in the serum of the model mice."
Notably, AKG reversed the declined levels of three key regulators, SIRT1, PGC-1Ξ±, and Nrf2, involved in supporting mitochondrial health and antioxidant defenses.
"Although D-gal induction treatment reduced the expression of SIRT1, PGC-1Ξ± and Nrf2 of skeletal muscle relative to the control group, AKG treat significantly elevated the expression."
The findings show that AKG boosts antioxidant defenses in muscle, suggesting it helps protect aging mice from oxidative damage.
Conclusion
This study provides strong evidence that AKG improves muscle mass, structural integrity, performance, and resilience in aging muscle. Its ability to support protein homeostasis and protect key stress-response pathways highlights its potential as a therapeutic candidate for age-related muscle loss.
"AKG could regulate protein homeostasis, thereby enhancing the protein composition and size of myofibersβ¦"
"...AKG enhanced SOD activity⦠and scavenged reactive oxygen species (ROS) by activating the SIRT1/PGC-1α/Nrf2 pathway, thereby improving mitochondrial function."
Breakthrough longevity research on alpha-ketoglutarate has demonstrated its multifaceted benefits across various aspects of aging, positioning it as a promising compound for comprehensive anti-aging interventions beyond muscle health alone.
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