Exacerbations in Chronic obstructive pulmonary disease (COPD) are often accompanied by pulmonary and systemic inflammation, and are associated with an increased susceptibility to weight loss and muscle wasting. As the emphysematous phenotype in COPD appears prone to skeletal muscle wasting, the aims of this study were to evaluate in emphysematous compared to control mice following repetitive exacerbations (1) changes in muscle mass and strength and, (2) whether muscle mass recovery and its underlying processes are impaired. Emphysema was induced by intra-tracheal (IT) elastase instillations, followed by three weekly IT-LPS instillations to mimic repetitive exacerbations. Loss of muscle mass and strength were measured, and related to analyses of muscle protein turnover and myogenesis signaling in tissue collected during and following recovery. Emphysematous mice showed impaired muscle mass recovery in response to pulmonary inflammation-induced muscle atrophy. Proteolysis and protein synthesis signaling remained significantly higher in emphysematous mice during recovery from LPS. Myogenic signaling in skeletal muscle was altered, and fusion capacity of cultured muscle cells treated with plasma derived from LPS-treated emphysematous mice was significantly decreased. In conclusion, repetitive cycles of pulmonary inflammation elicit sustained muscle wasting in emphysematous mice due to impaired muscle mass recovery, which is accompanied by aberrant myogenesis.