Genetically modified mice with Gsα-specific deficiency in skeletal muscle showed reduced glucose tolerance, muscle atrophy and force reduction, along with a fast-to-slow fiber type switch (Chen et al., AJP 296:C930-40, 2009). We further investigated a hypothesis that the switching to more slow fibers is an adaptive response with functional significance. Corresponding to the muscle type switch evident by myosin isotyping, the thin filament regulatory proteins troponin T and troponin I both had significant changes to their slow isoforms in the atrophic soleus muscle of 3-month-old Gsα-deficient mice. This fiber type switching progressed and soleus muscles of one-year-old Gsα-deficient mice expressed only slow isoforms of troponin. Functional characterization of soleus muscle of 3-month-old Gsα-deficient mice showed slower contractile and relaxation velocity in twitch and tetanic contractions than wild type controls. Examination of fatigue tolerance showed that Gsα-deficient soleus muscle was more resistant to intermittent fatigue stimulation with faster and better recovery as compared with wild type controls. Our results suggest that fast-to-slow type switch improves fatigue resistance of skeletal muscle as a compensatory adaptation to muscle glucose intolerance and atrophy in Gsα-deficiency, suggesting a mechanism for improving muscle function in diabetic patients.