The Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Therapy on Skeletal Muscle Lipid Content in Obese and Nonobese Men

Abstract

Obstructive sleep apnea (OSA), independently of obesity (OBS), predisposes to insulin resistance (IR) for largely unknown reasons. Since OSA-related intermittent hypoxia triggers lipolysis, overnight increases in circulating free fatty acid (FFA) including palmitic acid (PA) may lead to ectopic intramuscular lipid accumulation potentially contributing to IR. Using 3-T-1H-magnetic-resonance-spectroscopy, we therefore compared intra- and extra-myocellular lipid (IMCL and EMCL) in vastus lateralis muscle at ~7:00 a.m. between 26 male patients with moderate-to-severe OSA (17 obese, 9 non-obese) and 23 healthy male controls (12 obese, 11 non-obese). Fiber type composition was evaluated by muscle biopsies. Moreover, we measured fasted FFA including PA, HbA1c, thigh subcutaneous fat volume (ScFAT, 1.5-T-magnetic-resonance-tomograpphy) and maximal oxygen uptake (VO2max). 14 patients were reassessed after continuous-positive-airway-pressure (CPAP) therapy. Total FFA and PA were significantly by 178% and 166% higher in OSA patients vs. controls and correlated with the apnea-hypopnea index (AHI) (r≥0.45, P<0.01). Moreover, IMCL and EMCL were 55% (P<0.05) and 40% (P<0.05) higher in OSA patients, i.e. 114% and 103% in non-obese, 24.4% and 8.4% in obese subjects (with higher control levels). Overall, PA, FFA (minus PA) and ScFAT significantly contributed to IMCL (multiple r=0.568, P=0.002). CPAP significantly decreased EMCL (-26%) and, by trend only, IMCL, total FFA and PA. Muscle fiber composition was unaffected by OSA or CPAP. Increases in IMCL and EMCL are detectable at ~7:00 a.m. in OSA patients and partly attributable to overnight FFA excesses and high ScFAT or BMI. CPAP decreases FFAs and IMCL by trend but significantly reduces EMCL.

The Association of Obstructive Sleep Apnea and Nocturnal Hypoxemia with Lipid Profiles in a Population-Based Study of Community-Dwelling Australian Men

“…Triglycerides were specifically analyzed due to a strong relationship between waist circumference and triglycerides, likely mediated through insulin resistance 41 and due to the minimal effects of lipid lowering therapies compared to other lipid measures. We further conducted binary logistic regression to determine associations between clinical categories of OSA [no OSA <10/hr, mild (10-19/hr), moderate (20-29/hr) and severe (≥30/hr) (27)] and the categorized dependent variable -triglyceride (≥ 1.7mmol/L).…”

“…25,26 Supporting this, a recent study using early morning 3-T-1 H-magnetic resonance spectroscopy of the vastus lateralis muscle in men reported substantial and most likely transient increases of intramyocellular and extramyocellular lipids in non-obese men with OSA compared to participants without OSA. 27 Consequently, we conducted analyses stratified by waist circumference to observe an obesity-independent association between OSA metrics and dyslipidemia.…”

“…54 Insulin inhibits hepatic triglyceride production and animal studies have also demonstrated a link between intermittent hypoxia and insulin resistance in lean mice. 55,56 In human studies, Koenig et al 27 recently reported large overnight CIH-related increases in plasma triglycerides that occurred in non-obese participants with OSA compared to participants with obesity and OSA (214.7 ±40.9 cf 95.6 ± 12.6 mg/100mL), and speculate that muscle or liver free fatty acid uptake capacity may be exceeded by overnight increases in circulating FFAs and may therefore be associated with re-esterification of FFAs. In a small clinical study of 15 "healthy" men with severe OSA (mean WC: 97cm, BMI: 28.4 kg/m 2 ; free of significant comorbidities), Drager et al 57 reported disturbances in triglyceride-rich lipoprotein metabolism, with correction of delayed fractional clearance rates (FCR) of radiolabeled triglycerides and cholesteryl ester by 3 months of CPAP therapy supporting their earlier work.…”

Obstructive Sleep Apnoea and Lipid Metabolism: The Summary of Evidence and Future Perspectives in the Pathophysiology of OSA-Associated Dyslipidaemia

“…The fractional clearance rate (FCR) of TG showed a 5-fold increase after 3-month CPAP therapy, but the FCR of CE was unchanged [ 109 ]. Circulating FFAs, which are the markers of increased lipolysis, were decreased after CPAP [ 345 ]. In line with this, CPAP withdrawal dynamically increased nocturnal FFA levels [ 346 ].…”

Muscle Lipid Oxidation Is Not Affected by Obstructive Sleep Apnea in Diabetes and Healthy Subjects

“…Our results complement a recent study showing (in agreement with the present study) that OSA worsens glucose homeostasis. However, other authors also observed increased intra- and extramyocellular lipid content in skeletal muscle [ 61 ]. An increased triglyceride accumulation and modified lipidomic profile in myocytes after hypoxic exposure has been documented in vitro, presumably partly due to de novo lipogenesis [ 59 , 60 ].…”