Inflammation Factors Mediate Association of Muscle Mass and Migraine: NHANES 1999–2004 and Mendelian Randomization

Chunyan Jia, Hong Li, Shaonan Yang, Yue Liu, Lijun Liu, Aijun Ma, Liang Zhang Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Liang Zhang, Department of Neurology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, Shandong, 266071, People’s Republic of China, Tel +86-178-5329-7291, Email [email protected] Lijun Liu, Department of Neurology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, Shandong, 266071, People’s Republic of China, Tel +86-178-5329-0950, Email [email protected]: The relationship between adipose-muscle distribution and its effect on migraine remains unclear. This study examines the association between muscle mass and migraine prevalence and evaluates potential mediation by systemic inflammatory biomarkers.Methods: Using a cross-sectional design, we analyzed data from 10,400 participants in the National Health and Nutrition Examination Survey (NHANES) (1999– 2004). The association between appendicular lean mass normalized to body mass index (ALM/BMI) and migraine prevalence was evaluated through weighted logistic regression and subgroup analyses. Mediation analyses were conducted to examine the potential mediating roles of inflammatory markers, including C-reactive protein (CRP), white blood cell count (WBC), and neutrophils, in the relationship between ALM/BMI and migraine prevalence. Genetic causality was investigated via two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) data.Results: 20% of total participants reported migraines. A higher ALM/BMI ratio was inversely associated with migraine after full adjustment (OR = 0.243; 95% CI: 0.122– 0.487, p < 0.001). Vigorous activity reduced migraine susceptibility by 24% (OR = 0.760; 95% CI: 0.663– 0.872, p < 0.001). CRP, WBC and neutrophils mediated 2.0% (p = 0.024), 3.1% (p = 0.011), and 2.8% (p = 0.019) of the ALM/BMI-migraine association, respectively. The inverse-variance weighted approach (IVW) in MR analysis indicated that higher basal metabolic rate (BMR) reduced migraine risk (OR = 0.996, 95% CI: 0.992– 0.998, p = 0.004) and headache risk (OR = 0.998, 95% CI: 0.997– 1.000, p = 0.018). Fat-free mass also exhibited protective effects on migraines (OR = 0.997, 95% CI: 0.994– 1.000, p = 0.045).Conclusion: Increased muscle mass is associated with reduced migraine risk, partially mediated by attenuating systemic inflammation. These findings provide us with an approach of health management to prevent migraines.Keywords: appendicular muscle mass, basal metabolic rate, migraine, inflammation, national health and nutrition examination survey, Mendelian randomization