This thesis investigated the roles of the NKCC and Na+/K + ATPase in the volume regulatory response of resting mammalian skeletal muscle during hypertonic challenge. Study 1 demonstrates that skeletal muscle from adult mice regulates cell volume in response to both hypertonic and hypotonic stress. During hypertonic stress, cell shrinkage is followed by a regulatory volume increase (RVI) and cell swelling is followed by a regulatory volume decrease (RVD). The RVI is bumetanide sensitive consistent with primary involvement of the NKCC. Fast twitch (EDL) muscle lost more volume and took longer to recover volume compared to slow twitch (SOL) muscle. In study 2, the volume regulatory response was shown to be ouabain and bumetanide sensitive, consistent with primary involvement of the NKCC and secondary involvement of the Na +/K+ ATPase. Dystrophin deficient mouse (mdx) muscle shows an impaired ability to regulate volume compared to wild type mice and this impairment appears to reside primarily with the NKCC and its activation pathway. The regulatory volume response of fast twitch (EDL) muscle appears to be prolonged and undergoes greater magnitudes of volume change compared to slow twitch (SOL) muscle. This suggests that slow twitch; primarily postural muscle is more tightly regulated in its volume regulatory response than fast twitch, locomotive muscle. Collectively, this thesis research provides further evidence that skeletal muscles regulate volume during challenges of extracellular tonicity. It also served to establish a model with which to study skeletal muscle volume regulation in both healthy and diseased animals.