The Limb Girdle Muscular Dystrophies (LGMD) are a genetically heterogeneous group of disorders that affect muscle structure and strength. Although the general clinical phenotype is similar across subtypes, age of onset, severity, and disease progression can be variable even among patients harboring the same mutation. We hypothesize that mitochondrial function plays an important role in LGMD progression and speculate that mitochondrial dysfunction precedes overt pathophysiology. To begin to explore this, we performed a tandem mass tagging (TMT) quantitative proteomic analysis to compare protein expression profiles from quadriceps lysates of Sgcg-/- (LGMDR5) and wild-type adult mice at 7 weeks of age. A total of 3345 proteins were identified, 1406 of which had at least 1 unique peptide and a high fidelity score. 958 proteins had all abundance values present. Of these, 29 were significantly (p≤0.05) downregulated, 329 significantly (p≤0.05) upregulated and 600 showed no significant difference. STRING interaction network analyses of these misregulated proteins showed 15% are related to mitochondrial function. Panther Ontology Classification showed that 21.8% are involved in the oxidative stress response. RT-PCR assays confirmed several of the altered expression profiles related to mitochondrial function. Evaluations of isolated mitochondria from quadriceps of Sgcg-/- mice showed: significant (p≤0.05) decreases in protein expression of complex I (70%), II (68%), IV (67%), and V (18%), decreases in the oxygen consumption levels, decreased ATP production (53%); decreased mtDNA copy numbers (70%), and activity levels of complex I (70%), complex II (69%) and complex III (45%) compared to wild-type. This study provides important information regarding the influence of LGMD on mitochondrial function at the early stages of disease development. Future evaluations of how these parameters change with disease progression will yield information that will guide therapeutic development focused on the mitochondrial aspects of LGMD.