Targeting the mTOR-mitochondrial function axis: Calcitriol attenuates sarcopenic obesity with lipid dysregulation etiology.

Abstract

Sarcopenic obesity (SO) manifests as intramuscular lipid deposition and regenerative impairment triggered by dysregulation of the mitophagy-associated axis. Mitochondria-associated membranes (MAMs) are critical for lipid metabolism and mitochondrial function regulation. The mechanistic target of rapamycin (mTOR) is a functional protein at the MAMs and a central metabolic regulator; however, the underlying mechanisms by which mTOR dysregulation affects SO remain unclear. Calcitriol possesses the potential to improve mitochondrial function and fatty acid oxidation. This study investigated the mechanism of Calcitriol in SO using an in vivo SO mice model and an in vitro lipotoxicity-induced myoblast atrophy model. Calcitriol significantly ameliorated muscle atrophy in SO mice, as evidenced by increased grip strength, enhanced behavioral activity, and improved histopathological lesions. Untargeted metabolomic analysis revealed that Calcitriol intervention significantly ameliorated lipid metabolic disorders in SO mice, manifested by a marked reversal of aberrant changes in key lipid metabolites and the restoration of β-oxidation and mitochondrial function-related metabolites to physiological levels. Calcitriol treatment reduced pro-inflammatory cytokines while increasing anti-inflammatory cytokines, restored the contact distance between mitochondria and endoplasmic reticulum at MAMs, and enhanced mitophagy. RNA-Seq, molecular docking, and molecular dynamics simulations collectively demonstrated that these effects were attributable to mTOR downregulation. Furthermore, in vitro mTOR knockdown confirmed that Calcitriol ameliorates lipotoxicity-induced myoblast atrophy through an mTOR-dependent pathway, maintaining MAMs, stabilizing calcium homeostasis, mitigating mitochondrial dysfunction, and reducing ROS generation. In summary, this study demonstrates a novel mechanism whereby Calcitriol effectively inhibits mTOR, which is associated with the restoration of structural integrity of MAMs and the amelioration of disordered lipid metabolism, thereby attenuating SO.