BACKGROUND: Training volume is paramount in the magnitude of physiological adaptations following resistance training. However, patients with severe COPD are limited by dyspnea during traditional two-limb low-load/high-repetition resistance training (LLHR-RT), resulting in suboptimal training volumes. During a single exercise session, single-limb LLHR-RT decreases the ventilatory load and enables higher localized training volumes compared with two-limb LLHR-RT. RESEARCH QUESTION: Does single-limb LLHR-RT lead to more profound effects compared with two-limb LLHR-RT on exercise capacity (6-min walk distance (6MWD)), health status, muscle function, and limb IM adaptations in patients with severe COPD? STUDY DESIGN AND METHODS: Thirty-three patients (mean age 66 +/- 7 years; FEV1 39 +/- 10% predicted) were randomized to 8 weeks of single- or two-limb LLHR-RT. Exercise capacity (6MWD), health status, and muscle function were compared between groups. Quadriceps muscle biopsy specimens were collected to examine physiological responses. RESULTS: Single-limb LLHR-RT did not further enhance 6MWD compared with two-limb LLHR-RT (difference 14 (-12 to 39 m)). However, 73% in the single-limb group exceeded the known minimal clinically important difference of 30 m compared with 25% in the two-limb group (p = 0.02). Health status and muscle function improved to a similar extent in both groups. During training, single-limb LLHR-RT resulted in a clinically relevant reduction in dyspnea during training compared with two-limb LLHR-RT (-1.75; p = 0.01), but training volume was not significantly increased (23%; p = 0.179). Quadriceps muscle citrate synthase activity (19%; p = 0.03), hydroxyacyl-coenzyme A dehydrogenase protein levels (32%; p < 0.01), and capillary-to-fiber ratio (41%; p < 0.01) were increased compared with baseline after pooling muscle biopsy data from all participants. INTERPRETATION: Single-limb LLHR-RT did not further increase mean 6MWD compared with two-limb LLHR-RT, but it reduced exertional dyspnea and enabled more people to reach clinically relevant improvements in 6MWD. Independent of execution strategy, LLHR-RT improved exercise capacity, health status, muscle endurance, and enabled several physiological muscle adaptations, reducing the negative consequences of limb muscle dysfunction in COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; number NCT02283580; URL www.ClinicalTrials.gov.

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