To our knowledge, this is the first mendelian randomization study to systematically evaluate the causal relationships between sarcopenia-related traits and OSA in European population. Existing clinical studies have indicated that early-onset sarcopenia is more likely to occur in younger patients with OSA[21]. The sarcopenia index was negatively correlated with the odds ratio of sleep disorders. Maintaining optimal muscle mass may have a beneficial effect on OSA[22]. Our findings reveal that genetically determined low hand grip strength, falls, frailty, and disability are significantly associated with increased risks of OSA. Genetically predicted usual walking pace was negatively correlated with OSA, indicating that a lower walking speed increases the probability of suffering from sleep apnea. Additionally, muscle mass, fat mass, and water mass were positively related to OSA. However, we did not find a direct causal relationship between (left & right) hand grip strength, malnutrition, the duration and frequency of walking and OSA. Overall, the current MR results provide valuable insights into the impact of sarcopenia on OSA, highlighting the importance of considering skeletal muscle health in preventive and therapeutic strategies.
Observational investigations have demonstrated a transdiagnostic relationship between sleep duration and hand grip strength as well as the potential use of hand grip strength as a marker in OSA[23]. It also strongly endorses the effect of grip strength on OSA in MR analysis, revealing a causal association between sarcopenia and OSA. A cross-sectional study of Korean adults aged 40 to 80 years showed that low OSA risk was found to be associated with high grip strength after adjusting for other sleep parameters and confounders[24]. Another cross-sectional study involving Chinese individuals also reported that self-reported excessive daytime sleepiness accompanied by snoring or apnea was associated with the lowest grip strength[25]. Furthermore, a HypnoLaus cohort study based on a Swiss population found that severe OSA measured using polysomnography was associated with decreased muscle strength. In adults over 60 years of age, low muscle strength directly affected OSA[26]. This finding aligned with our MR results that the more severe the low grip strength condition in individuals over 60 years of age, the higher the risk of OSA. However, no association was found between left or right hand grip strength and OSA. Therefore, more extensive studies are still needed on the relationship between grip strength and OSA for different hand tests.
Previous studies have found that sleep apnea is associated with an increased risk of falls in older men[27, 28], independent of confounders. Sleep deprivation is a major cause of unintentional injuries from falls, but no studies have investigated whether the frequency of falls and the risk of falling increase the risk of OSA. Patients with sarcopenia experience decreased muscle strength, particularly in the lower limbs, leading to longer sitting or lying times[29]. Some studies have shown that a 20% reduction in muscle mass is associated with a reduced ability to perform activities of daily living and an increased risk of falls. The risk of death significantly increases when muscle mass loss reaches 40%. Our results suggest that falls is a risk factor for OSA, offering a new perspective for preventing OSA. Aging, inflammation, oxidative stress, and other factors may partially contribute to the development of sarcopenia and OSA[30, 31].
Treatment of frailty is an important approach to treating OSA, and sarcopenia is a major component of frailty[32]. Karla et al. found that a gender-stratified association between OSA risk and frailty in women but not in men[33]. Nevertheless, cross-sectional analyses from a prospective cohort study focusing on older men in the United States suggested that OSA was independently associated with greater evidence of frailty[34]. In addition, Omachi et al. reported that patients with OSA are at increased risk of recent work disability relative to patients without OSA[35]. In our study, a strong causal relationship was found between frailty, disability and OSA. This findings also strongly validate the above studies and provide a broader range of therapeutic strategies for OSA. In contrast, genome-wide association studies have not found a causal relationship between malnutrition and OSA. A retrospective intra-laboratory review of PSG data similarly confirmed that sleep-disordered breathing is common among the patients with muscular dystrophy (MD). Not all types of MD had the same degree of OSA or the same clinical manifestations. After adjusting for age, gender, body mass index and type, MD was marginally associated with OSA[36]. Although some reports have claimed that deficient vitamin D leads to a statistically higher risk of OSA, especially in children and adolescents[37]. However, evidence supporting the role of vitamin D and other nutritional indicators in adult OSA remains limited. Further research is needed to determine whether interventions for malnutrition can prevent the development of OSA.
Our MR study on the relationship of usual walking pace with OSA indicated that usual walking pace was a protective factor for OSA. A possible causal pathway for this finding involves the Rostral Fluid Shift hypothesis[38]. According to this hypothesis, during the day fluid accumulates in the intravascular and interstitial spaces of the legs due to gravity, and upon lying down at night redistributes rostrally, again owing to gravity. This fluid is displaced to the rostral side (towards the head), increasing the tendency to narrow the upper airway, thus predisposing to OSA[39]. Physical activity, such as walking, reduces fluid accumulation in the lower extremities, while increasing upper airway dilator muscle strength, reducing nasal resistance and improving sleep architecture[40]. A large population-based study also verified that a slower walking speed is associated with a greater prevalence of OSA[41]. Nevertheless, a large number of observational and cohort studies are needed to demonstrate the effect of walking duration and frequency on OSA.
Different body fat distribution is a genetic factor for OSA. Excess fat mass in the neck (often increasing with central obesity), as indicated by high neck circumferences, pressures the upper airway, leading to airway collapse and reduced lung volume[42, 43]. Moreover, in our study, excess fat content, whether in the limbs or trunk, also increases the risk of OSA. As visceral adipose tissue secretes abundant pro-inflammatory cytokines, Giovanna and her colleagues hypothesized interactions between obesity, pro-inflammatory cytokines (including IL-1, IL-6, and TNF-α), and OSA[44]. Fat mass continues to increase with age until about 70 years old, while muscle mass reduces from around 30. Rolland et al. reported that sarcopenic obesity increases the risk of decline in physical performance more than either sarcopenia or obesity alone[45].
ALM is a sarcopenia-related trait mainly affected by skeletal muscle and is more heritable than whole-body lean mass[46, 47]. Contrary to the study by Liu et al.[48], we found a genetic causal relationship between ALM and OSA. Additionally, our results indicated that higher limb, trunk, and whole-body fat mass increases the risk of OSA, similar to a study showing a positive correlation between OSA severity and the muscle skeletal index reported by Takeshi et al.[11]. More observational studies are needed to investigate the relationship between skeletal muscle and OSA. Interestingly, we also found a strong link between whole-body water mass and OSA. This observation aligns with the findings of Hsu et al.[49], which suggested that increased truncal adiposity and body water mass are associated with a higher risk of low arousal threshold obstructive sleep apnea.
While we adjusted for several potential confounding factors in our analyses, there may still be residual confounding or unmeasured variables that could influence the observed associations. Future studies incorporating additional covariates or using alternative analytical approaches may provide further insights into the causal pathways linking sarcopenia-related traits to OSA.