Abnormal intermuscular coordination has been highlighted in the field of post-stroke upper extremity (UE) rehabilitation. Relatively recent studies have quantified the altered "muscle synergies", distinctive co-activation patterns of a group of muscles, which characterize the stroke-induced abnormal intermuscular coordination. Nonetheless, whether targeting the altered muscle synergy(ies) would ameliorate the stroke-induced motor impairment and improve motor function remains unknown. Our ultimate aim is to design an exercise protocol that modifies abnormal muscle synergies and improves motor function in UE after stroke. In this study, the feasibility of an electromyographic (EMG) signal-guided exercise protocol, which targeted the alteration of an elbow flexor synergy, was tested in healthy subjects. Four neurologically intact adults participated in a six-week isometric exercise to activate two major elbow flexor muscles, biceps and brachioradialis, in isolation. Participants performed an isometric reaching in a virtual three-dimensional (3D) force space to assess any potential changes in muscle synergies during the assessment at week zero, two, four, and six of the training. EMGs of 12 UE muscles and 3D forces were collected simultaneously. A non-negative matrix factorization (NMF) was applied to the EMGs to identify synergies. From the third-to-fourth week of the training, when the participants intended to use the newly learned motor skill, they were able to activate the targeted muscle pair in isolation and induce the formation of newly emerging synergistic muscle groups. As the participants practiced to expand their repertoire of intermuscular coordination patterns, their motor control of the trained UE was improved. These findings suggest that our isometric exercise protocol can potentially modulate impaired muscle coordination in a way that benefits stroke survivor's performance in activities of daily living (ADLs) and, eventually, their quality of life.