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Background and aims Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. Methods Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. Results Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). Conclusions Whether suffering from "true" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted.

Numerous controversies surround the peptide hormone irisin. Although implicated as a myokine promoting the browning of adipose tissue in rodents, its roles in humans remain unclear. Contradictory results have also been found with respect to the relationships between adiposity or metabolic health and plasma irisin levels in humans. We investigated the relationship between irisin levels and body composition (hydrostatic weighing), insulin sensitivity (hyperinsulinemiceuglycemic clamp), fitness level (ergocycle VO2max) and skeletal muscle metabolic profile in 53 men (aged 34–53 years) from four groups: sedentary non-obese controls (body mass index [BMI] <25 kg/m2), sedentary obese (BMI >30 kg/m2), sedentary obese glucose-intolerant, and non-obese highly trained endurance active. Baseline plasma irisin levels were significantly different between groups, being lowest in trained men (140.6±38.2 ng/mL) and highest in metabolically deteriorated glucose-intolerant subjects (204.0±50.5 ng/mL; ANOVA p=0.01). Including all subjects, irisin levels were positively associated with adiposity (e.g. fat mass, r=0.430, p<0.01) and negatively associated with fitness (r=-0.369, p<0.01), insulin sensitivity (M/I, r=-0.355, p<0.01) and muscle citrate synthase (CS) activity (r=-0.482, p<0.01). Most correlations lost statistical significance when excluding active individuals, except for insulin resistance (r=-0.413, p<0.01) and CS (r=-0.462, p<0.01). Multiple regression analyses reveal CS as the strongest independent predictor of irisin levels (r2 range 0.214 to 0.237). We conclude that muscle oxidative potential is an important factor linked to circulating irisin levels. Keywords : Irisin . Myokine . Adipose tissue . Adipokine . Obesity. Insulin sensitivity