SOD1-G93A mice exhibit muscle-fiber-type-specific decreases in glucose uptake in the absence of whole-body changes in metabolism.

Background: Skeletal muscles play an important role in systemic glucose homeostasis and are purported to be the origin of the altered metabolic state observed in amyotrophic lateral sclerosis (ALS). Objective: The purpose of this study was to evaluate whole-body and muscle-specific glucose metabolism in the SOD1-G93A mouse model of ALS. Methods: We assessed glucose tolerance in early-, middle-, and late-stage SOD1-G93A and control mice using an intraperitoneal glucose tolerance test. We then measured the respiratory exchange ratio (CO2 production/O2 consumption) as a function of fasting and feeding using indirect calorimetry in a subset of male mice at these time points. Finally, muscles from all mice were harvested to evaluate basal and insulin-stimulated glucose transport in fast- and slow-twitch muscles. Results: No changes in systemic glucose clearance were observed in SOD1-G93A mice at any stage, nor were there changes in fasting insulin levels. Indirect calorimetry revealed an increase in the respiratory exchange ratio during the fed state at middle, but not at early or late stages of disease. Middle-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in fast-twitch, but not slow-twitch, skeletal muscle. Late-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in both fast- and slow-twitch muscle, as well as increased basal (non-insulin-stimulated) glucose uptake. Conclusions: These results suggest that alterations in muscle metabolism occur in a fiber-type-specific manner in ALS, but do not necessarily lead to whole-body metabolic changes in SOD1-G93A mice.