Obstructive sleep apnea (OSA) is a complex process that can lead to the dysregulation of the molecular clock, as well as 24 h rhythms of sleep and wake, blood pressure, and other associated biological processes. Previous work has demonstrated crosstalk between the circadian clock and hypoxia-responsive pathways. However, even in the absence of OSA, disrupted clocks can exacerbate OSA-associated outcomes (e.g., cardiovascular or cognitive outcomes). As we expand our understanding of circadian biology in the setting of OSA, this information could play a significant role in the diagnosis and treatment of OSA. Here, we summarize the pre-existing knowledge of circadian biology in patients with OSA and examine the utility of circadian biomarkers as alternative clinical tools.

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AMPK agonists, such as AICAR, are used in the treatment of diabetes since they mimic several effects of exercise such as a more oxidative phenotype and increased insulin sensitivity. Exercise training can increase muscle levels of heat shock protein 25 (Hsp25), which is associated with improvements in muscle function and insulin‐stimulated glucose uptake. In contrast decreased Hsp25 in skeletal muscle is associated with insulin resistance in rats. Evidence in animals and humans suggests the combination of exercise and AMPK‐activating drugs may decrease exercise‐training adaptations. These experiments compared the effects of AICAR on cardiorespiratory, muscular, and Hsp25 adaptations to forced (treadmill, TM) or voluntary (running wheel, RW) training. It was hypothesized that AICAR + TM or RW would attenuate increases in exercise capacity, muscle force, and Hsp25 expression compared to training alone. Adult, male C57 mice were divided into 6 groups (n = 8–10/group): 1‐Placebo, 2‐AICAR, 3‐Placebo + TM, 4‐Aicar + TM, 5‐Placebo + RW, 6‐Aicar + RW. Groups received daily placebo or AICAR with or without TM or RW over 7 days. Plantarflexor muscle force and fatigue (% of max force after 10 contractions) were measured in vivo and exercise capacity was assessed with pre‐ and post‐ treadmill tests. Muscle Hsp25 protein levels were quantified with western blot. AICAR significantly reduced average daily RW distance vs. placebo, 1099±133 and 1923±103 m/day, respectively. AICAR + TM did not affect training‐associated increases in exercise capacity compared to Placebo + TM (Δ time pre to post: 903 ± 164 vs. 1,188 ± 99 sec. for AICAR and Placebo, respectively, p<0.05); however, AICAR + RW attenuated the increases in exercise capacity compared to Placebo + RW (Δ time pre to post: 710 ± 134 vs. 921 ± 87 sec. for AICAR and Placebo, respectively, p<0.05). Muscle force was increased with AICAR in TM or sedentary groups compared to placebo while AICAR + RW was associated with reduced muscle force compared to Placebo + RW (Placebo: 1.2 ± 0.07 vs. 1.3 ± 0.07 vs. 1.4 ± 0.08 and AICAR: 1.4 ± 0.08 vs. 1.5 ± 0.12 vs. 1.1± 0.11 g/g body mass, for sedentary, TM, and RW, respectively, p<0.05). Fatigability was greater with AICAR in sedentary mice; however, AICAR + TM decreased fatigability compared to AICAR alone (p<0.05). TM or RW increased Hsp25 levels in both placebo and AICAR groups compared to sedentary placebo (Placebo: 0.09 ± 0.01 vs. 0.15 ± 0.01 vs. 0.15 ± 0.02 and AICAR 0.15 ± 0.02 vs. 0.17 ±0.02 vs. 0.19 ± 0.03 AU, for sedentary, TM, and RW, respectively, p<0.05) and AICAR increased Hsp25 in the sedentary group compared to placebo (0.15 ± 0.02 vs. 0.09 ± 0.01 AU, p<0.05). These findings suggest AICAR does not impair cardiorespiratory or muscular adaptations to forced exercise while AICAR reduced RW distance and training associated adaptations to voluntary exercise. AICAR in combination with forced or voluntary exercise did not impair Hsp25 increases and AICAR alone mimics exercise induced Hsp up‐regulation in sedentary muscle and may ...

Individuals with hypercholesterolemia are at an increased risk for developing heart disease and are commonly prescribed statin medications, the most effective cholesterol‐lowering drugs, as well as exercise. Common adverse effects of statins include muscle pain and/or dysfunction, that may be exacerbated with exercise. Both exercise training and statins have been associated with reductions in inflammatory cytokines such as interleukin‐6 (IL‐6). To date, no studies have investigated if hypercholesterolemia alone impacts muscular and cardiorespiratory adaptations to treadmill training and how statin treatment may alter these adaptations. We hypothesized that hypercholesterolemia alone would impair muscular and cardiorespiratory adaptations to treadmill training, and such impairments would be exacerbated with statin treatment. Adult ApoE−/− mice with genetically high cholesterol were divided into 4 groups (n= 5–6/group) and completed 14d of treadmill training (60 min/day) or remained sedentary while receiving daily placebo or atorvastatin. Cardiorespiratory adaptations were assessed by pre‐ and post‐maximal treadmill tests. After 14d, muscle function was analyzed in vivo by measuring strength and fatigability (% of maximal force after 10 contractions) with a dual mode footplate system. Data were analyzed with 2‐way ANOVAs and post‐hoc tests. After testing, hindlimb muscles and hearts were harvested and frozen for Elisa assays to quantify IL‐6 and vascular endothelial growth factor (VEGF). Atorvastatin was associated with decreased maximal isometric force relative to body or gastrocnemius mass in both sedentary and treadmill groups (1.44±0.10 vs. 1.15±0.16 and 1.51±0.07 vs. 1.22±0.21 g/g body mass, respectively, p<0.05). Muscle fatigability was similar among all conditions; average group values ranged from 33%‐34% of maximum. Cardiorespiratory fitness increased in both treadmill groups with 12:17±6:36 and 12:56±4:23 min increases in maximal test time for placebo and statin groups, respectively (p<0.05). Maximal test time was unchanged in sedentary groups. Treadmill training decreased respective muscle IL‐6 and VEGF levels by 87 and 64% and 50 and 45% compared to sedentary, in placebo and statin groups, respectively (p<0.05). Treadmill training decreased heart IL‐6 32 and 50% compared to sedentary, in placebo and statin groups, respectively (p<0.05). Training decreased heart VEGF 41% in placebo group only (p<0.05). These findings suggest statin treatment impairs muscle strength in both sedentary and treadmill‐trained hypercholesterolemic mice, but does not alter muscle fatigue or cardiorespiratory adaptations to exercise training. Additionally, statins did not affect training‐associated reductions in the inflammatory cytokine, IL‐6. Further research is needed to determine biological and/or cellular mechanisms whereby statin medications affect muscular strength independent of muscular and cardiorespiratory endurance.Support or Funding InformationAPS STRIDE Fellowship Program and Grant #1 R25 HL115473‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.