High-Fat Diet-Induced Mitochondrial Dysfunction Promotes Genioglossus Injury – A Potential Mechanism for Obstructive Sleep Apnea with Obesity

Abstract

Purpose Obesity is a worldwide metabolic disease and a critical risk factor for several chronic conditions. Obstructive sleep apnea (OSA) is an important complication of obesity. With the soaring morbidity of obesity, the prevalence of OSA has markedly increased. However, the underlying mechanism of the high relevance between obesity and OSA has not been elucidated. This study investigated the effects of obesity on the structure and function of the genioglossus to explore the possible mechanisms involved in OSA combined with obesity. Methods Six-week-old male C57BL/6J mice were fed high-fat diet (HFD, 60% energy) or normal diet (Control, 10% energy) for 16 weeks. The muscle fibre structure and electromyography (EMG) activity of genioglossus were measured. The ultrastructure and function of mitochondrial, oxidative damage and apoptosis in genioglossus were detected by transmission electron microscopy (TEM), qPCR, Western blotting, immunohistochemistry and TUNEL staining. We further studied the influence of palmitic acid (PA) on the proliferation and myogenic differentiation of C2C12 myoblasts, as well as mitochondrial function, oxidative stress, and apoptosis in C2C12 myotubes. Results Compared with the control, the number of muscle fibres was decreased, the fibre type was remarkably changed, and the EMG activity had declined in genioglossus. In addition, a HFD also reduced mitochondria quantity and function, induced excessive oxidative stress and increased apoptosis in genioglossus. In vitro, PA treatment significantly inhibited the proliferation and myogenic differentiation of C2C12 myoblasts. Moreover, PA decreased the mitochondrial membrane potential, upregulated mitochondrial reactive oxygen species (ROS) levels, and activated the mitochondrial-related apoptotic pathway in myotubes. Conclusion Our findings suggest that a HFD caused genioglossus injury in obese mice. The mitochondrial dysfunction and the accompanying oxidative stress were involved in the genioglossus injury, which may provide potential therapeutic targets for OSA with obesity.

Chronic Intermittent Hypoxia-Induced Dysmetabolism Is Associated with Hepatic Oxidative Stress, Mitochondrial Dysfunction and Inflammation

“…In addition, we also show that the enzymatic activity of complexes I and II tends to increase in the CIH group. Chen et al [49] also observed a reduction in the mitochondria number in the genioglossus, the largest upper airway dilator muscle whose function is altered in patients with OSA. Also, the increase in FFA, a hallmark related to the increase in hepatic steatosis, can be contributing to mitochondrial damage and, therefore, to the reduction in mitochondria levels in these conditions [13].…”

Weight cycling based on altered immune microenvironment as a result of metaflammation

“…Metaflammation is closely linked to intestinal barrier dysfunction [ 113 ]. ROS has effects not only in the intestine but also in skeletal muscle, where it can inhibit glucose oxidative metabolism and lead to mitochondrial dysfunction [ 114 ]. The effect of WC begins with the destruction of the intestinal barrier, followed by the deposition and expansion of adipose tissue in the skeletal muscle, causing local hypoxia and excessive ROS, affecting the function and structure of the skeletal muscle, emphasizing the "dominant position" of fat, and finally resulting in diseases characterized by metastasis.…”

Obstructive Sleep Apnea and Role of the Diaphragm

“…The deformation of GG (movement) is less in patients than in subjects without OSA (less than about 1 millimeter on average); this reflects the presence of hypotonia (fibrosis, hypotrophy, phenotypic alteration, and myopathy), and the direct relationship between GG dysfunction and higher critical pressure (Pcrit) values [100,101]. In an animal model fed with many lipids, GG resulted in a numerical reduction of contractile fibers, a phenotypic imbalance (more white fibers), a reduction in mitochondrial function, and the presence of oxidation and apoptosis [102]. With OSA and advancing age, GG shows a lower myocellular repair capacity and more pronounced frailty in the face of hypoxia [103].…”