Calprotectin Is a Circulating Biomarker and Potential Therapeutic Target for Sarcopenia in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Sarcopenia, an important complication of chronic obstructive pulmonary disease (COPD), is significantly associated with increased mortality. Systemic inflammation is an important trigger of COPD-related skeletal muscle dysfunction. Calprotectin is a damage-associated molecular pattern involved in the inflammatory response, but its exact role and mode of action in COPD-related skeletal muscle dysfunction remain unclear. This study aimed to determine whether calprotectin is involved in COPD-related sarcopenia. METHODS: In this study, 235 patients with stable COPD were divided into the development (n = 117) and validation (n = 118) groups, and serum calprotectin concentrations were measured by enzyme-linked immunosorbent assays (ELISAs). Paquinimod, an oral calprotectin-specific inhibitor, was used to investigate the involvement of calprotectin in cigarette smoke (CS)-induced skeletal muscle dysfunction in vivo. RESULTS: Handgrip strength and quadriceps muscle strength, essential indicators of muscle strength, were negatively correlated with serum calprotectin levels (r = -0.367, p < 0.001; r = -0.409, p < 0.001). The 5-time sit-to-stand test results, which reflect endurance and physical strength, were positively correlated with serum calprotectin levels (r = 0.290, p = 0.006). Ultrasound measurement of the rectus femoris muscle revealed negative correlations of serum calprotectin levels with both muscle thickness (r = -0.448, p < 0.001) and cross-sectional area (r = -0.495, p < 0.001). Furthermore, serum calprotectin levels were significantly greater in patients with sarcopenia than in those without sarcopenia (90.09 ± 25.72 ng/mL vs. 59.56 ± 23.22 ng/mL, p < 0.001). Importantly, serum calprotectin levels could effectively predict sarcopenia in COPD patients in the development set (AUC = 0.811) and validation set (AUC = 0.805). In C57BL/6 mice with CS-induced muscle dysfunction, paquinimod (10 mg/kg/day) reduced CS-induced muscle mass loss (skeletal muscle weight 1.15% ± 0.09% vs. 1.33% ± 0.09%; p = 0.005) and increased the muscle cross-sectional area (1375 ± 536.9 μm2 vs. 2094 ± 470.2 μm2; p < 0.001). Paquinimod also reduced CS-induced muscle weakness, as indicated by increased grip strength (214.9 ± 31.38 g vs. 333.1 ± 34.93 g; p < 0.01). Paquinimod inhibited ubiquitin-proteasome system activity, reduced protein degradation marker levels, attenuated oxidative stress and increased antioxidant enzyme levels in CS-exposed mice. CONCLUSIONS: Serum calprotectin levels can be used to accurately predict sarcopenia in patients with COPD, and the calprotectin inhibitor paquinimod is a potential treatment for CS-induced skeletal muscle dysfunction.