We aimed to compare acute mechanical and metabolic responses of the diaphragm and rib cage inspiratory muscles during two different types of respiratory loading in patients with COPD. METHODS: In 16 patients (age:65±13, 56% male, FEV1:60±6%pred, Pimax:82±5%pred) assessments of respiratory muscle electromyography (EMG), esophageal (Pes) and gastric (Pga) pressures, breathing pattern, and noninvasive assessments of systemic (VO2, cardiac output, oxygen delivery and extraction) and respiratory muscle hemodynamic and oxygenation responses (blood flow index [BFI], oxygen delivery index, deoxyhemoglobin concentration [HHb] and tissues oxygen saturation [StiO2]), were performed during hyperpnea and loaded breathing. RESULTS: During hyperpnea, breathing frequency, minute ventilation, esophageal and diaphragm pressure-time product (PTP)/min, cardiac output and VO2 were higher than during loaded breathing (P<0.05). Average inspiratory Pes and Pdi per breath, scalene (SCA), sternocleidomastoid (SCM), and intercostal muscle activation were higher during loading breathing compared to hyperpnea (P<0.05). Higher Pdi during loaded breathing compared to hyperpnea was mostly due to higher inspiratory Pes (P<0.05). Diaphragm activation, inspiratory and expiratory Pga and rectus abdominis muscle activation did not differ between the two conditions (P>0.05). SCA-BFI and oxygen delivery index were lower, and SCA-HHb was higher during loaded breathing compared to hyperpnea. Furthermore, SCA and intercostal muscle StiO2 were lower during loaded breathing compared to hyperpnea (P<0.05). CONCLUSION: Greater inspiratory muscle effort during loaded breathing evoked larger ribcage and neck muscle activation compared to hyperpnea. In addition, lower SCA and intercostal muscle StiO2 during loaded breathing compared to hyperpnea indicates a mismatch between inspiratory muscle oxygen delivery and utilization induced by the former condition.