-Sarcoglycan is a transmembrane glycoprotein of the dystrophin complex located at skeletal and cardiac muscle sarcolemma. Defects in the -sarcoglycan gene (Sgca) cause the severe human type 2D limb girdle muscular dystrophy (LGMD-2D). Sgca-null mice develop progressive muscular dystrophy similar to human disorder, thus being a valuable animal model to investigate the physiopathology of the disorder. In this study, biochemical and functional properties of fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles of the Sgca-null mice were analyzed. EDL muscle of Sgca-null mice showed twitch and tetanic kinetics comparable to those of wild-type controls. In contrast, soleus muscle showed reduction of twitch half-relaxation time, prolongation of tetanic half-relaxation time and increase of maximal rate of rise of tetanus. EDL muscle of Sgca-null mice demonstrated a marked reduction of specific twitch and tetanic tensions and a higher resistance to fatigue compared to controls, changes that were not evident in dystrophic soleus. Contrary to EDL fibers, soleus muscle fibers of Sgca-null mice distinctively showed right shifts of the pCa-tension relationships and reduced sensitivity to caffeine of sarcoplasmic reticulum. Both EDL and soleus muscles showed striking changes in myosin heavy chain (MHC) isoform composition, while EDL showed a larger number of hybrid fibers than soleus. In contrast to the EDL, soleus muscle of Sgca-null mice contained a higher number of regenerating fibers and, thus, higher levels of embryonic MHC. In conclusion, the study revealed profound distinctive biochemical and physiological modifications in fast- and slow-twitch muscles resulting from -sarcoglycan deficiency.