(490a) Loss of GPR81 Is Associated with Impaired Fatty Acid Metabolism and Skeletal Muscle Aging

Skeletal muscle aging, or sarcopenia, is characterized by age-associated loss in skeletal muscle mass and strength. One of the hallmarks of skeletal muscle senescence is fat infiltration or myosteatosis, leading to enhanced lipid accumulation and impaired fatty acid metabolism. Accumulation of intramyocellular lipids (IMCLs) has been associated with enhanced insulin resistance and inflammation in the muscle. Understanding the mechanisms leading to impaired lipid metabolism and developing therapies to reverse or prevent myosteatosis might be crucial for healthy aging of the skeletal muscle.

The novel lactate receptor GPR81 has been shown to govern adipocyte fatty acid metabolism, but its function in skeletal muscle is eluded. We found that GPR81 expression is significantly reduced as human skeletal muscle cells senesce. Knockdown of GPR81 in young healthy myoblasts lead to a senesce-like phenotype, resulting in increased expression of key senescence hallmarks such as SaβGal, γH2AX, ROS accumulation, and impaired ability to differentiate to myotubes. Additionally, loss of GPR81 was detrimental for skeletal muscle metabolism. Seahorse assay confirmed that GPR81 knockdown lead to diminished mitochondrial activity, as confirmed by decreased oxygen consumption rate (OCR) as well as endogenous and exogenous fatty acid oxidation. This was accompanied by an increase in lipid accumulation and impaired autophagy. In all, loss of GPR81 lead to mitochondrial dysfunction and accelerated senescence in human myoblasts. Hence, we hypothesized that chemical agonists of GPR81 could reverse hallmarks of aging in human skeletal muscle cells. To this end, we treated aged myoblasts with the GPR81 agonists- 3-chloro-5-hydroxy BA (CHBA) and GPR81 agonist 2 (C2) for 10 days. Interestingly, both CHBA and C2 significantly decreased ROS accumulation and enhanced their ability to differentiate to myotubes. Mitochondrial dysfunction was ameliorated as confirmed by increased oxygen consumption rate and fatty acid oxidation. Next, to confirm the effect of GPR81 agonist on aging in-vivo, we utilized the progeric mouse model (LAKI) of aging. CHBA administration in LAKI mice significantly enhanced isometric force production and grip strength, accompanied by improvement in overall health of the mice.

In conclusion, our study shows that the lactate receptor GPR81 is essential for skeletal muscle function, and agonists of GPR81 may be promising therapeutic candidates to ameliorate skeletal muscle senescence.