Aging cellAug 2, 2026

Activating the Lactate Receptor GPR81 May Reduce Aging Signs and Improve Muscle Function in Cell and Accelerated Aging Models

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 3, 2026

Abstract

Loss of the lactate receptor GPR81 is associated with impaired lipid oxidation and enhanced lipid accumulation in aging muscle.

In cellular and progeroid models of muscle aging, loss of GPR81 led to increased lipid buildup and decreased lipid burning.
Knockdown of GPR81 in young myoblasts resulted in higher levels of DNA damage and reactive oxygen species, indicating stress.
Treatment with GPR81 agonists improved lipid oxidation in senescent myoblasts, decreasing lipid accumulation and enhancing muscle cell function.
Progeric mice treated with GPR81 agonists showed notable improvements in muscle regeneration and overall health.
GPR81 appears to play a significant role in managing lipid levels in skeletal muscle, which may be crucial for addressing age-related muscle decline.

Simplified

Skeletal muscle aging is associated with increased lipid accumulation, or myosteatosis, leading to lipotoxicity and loss of muscle function. Here, we report that loss of the lactate receptor GPR81 in cellular and progeroid models of muscle aging is associated with impaired lipid oxidation and enhanced lipid accumulation. Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), impaired mitochondrial activity, and autophagy. Conversely, treatment of senescent myoblasts with GPR81 agonists enhanced lipid oxidation, leading to a decrease in lipid accumulation, ultimately resulting in decreased DNA damage, ROS accumulation, and enhanced ability to form myotubes. In agreement with our in vitro findings, we observed significant improvement in muscle regeneration and overall health of progeric mice that were treated with GPR81 agonists. Our findings suggest that GPR81 plays a key role in skeletal muscle lipid metabolism, and agonists of GPR81 might play a promising role in reversing age-associated lipid accumulation and loss of muscle function.

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Activating the Lactate Receptor GPR81 May Reduce Aging Signs and Improve Muscle Function in Cell and Accelerated Aging Models

Abstract

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