Upper airway dilator muscle dysfunction in obesity: role of the ATF5–LONP1 axis in lipotoxic stress and exercise-associated functional recovery

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Obesity-related lipotoxic stress is associated with upper-airway dilator muscle dysfunction, yet endogenous stress responses governing mitochondrial quality control remain poorly defined. We investigated activating transcription factor 5 (ATF5)–Lon peptidase 1 (LONP1) signaling in mitochondrial quality control under lipotoxic stress, as well as its association with exercise-associated functional recovery. Clinical data from 1,546 adults were analyzed using multivariable models and propensity score-matched sensitivity analyses. Palatopharyngeal muscle specimens from 10 participants with obesity and 10 normal-weight controls were examined. Diet-induced obesity (DIO) mice underwent sternohyoid contractility and plethysmography testing; a 12-week swimming group was compared with sedentary DIO and dietary-reversal (DIO-DR) groups. Palmitic acid-treated C2C12 myotubes were used for mechanistic studies, combining ATF5 and LONP1 gain- and loss-of-function approaches, mitochondrial assays, chromatin immunoprecipitation sequencing, promoter assays, and autophagic-flux analysis. Obesity was associated with elevated circulating creatine kinase (CK) and lactate dehydrogenase (LDH). Greater metabolic burden was independently associated with higher CK, LDH, and myoglobin, but not with high-sensitivity cardiac troponin I (hs-cTnI) or creatine kinase-MB (CK-MB). Palatopharyngeal muscle from participants with obesity showed altered myofiber morphology and reduced myosin heavy chain (MyHC) immunoreactivity. DIO sternohyoid muscle exhibited lipid accumulation, mitochondrial abnormalities, and contractile dysfunction. In C2C12 myotubes, lipotoxic stress promoted nuclear ATF5 accumulation and occupancy at a conserved basic leucine zipper (bZIP) motif in the Lonp1 promoter. ATF5 overexpression improved mitochondrial respiration, redox–calcium homeostasis, and MyHC expression, whereas LONP1 knockdown attenuated these effects, and LONP1 overexpression partially reproduced this protective phenotype. Despite comparable final body weight and metabolic profiles between dietary-reversal and swimming-exercised groups, swimming produced greater improvements in sternohyoid force, inspiratory flow, and oxidative capacity, accompanied by enhanced ATF5–LONP1-associated mitochondrial stress-response markers. The findings support the ATF5–LONP1 axis as part of an adaptive mitochondrial stress response that contributes to exercise-associated recovery from obesity-related upper-airway muscle dysfunction. Mitochondrial quality control may represent a candidate translational target for obesity-related obstructive sleep apnea (OSA). Not applicable.

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