SOD1-G93A Mice Exhibit Muscle-Fiber-Type-Specific Decreases in Glucose Uptake in the Absence of Whole-Body Changes in Metabolism

Abstract

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.

A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis

“…Indeed, high incidences of glucose intolerance have been observed in patients diagnosed with sporadic ALS . However, as basal glucose uptake in extensor digitorum longus (EDL: another glycolytic muscle) of the SOD1 G93A mouse model of ALS is normal before overt denervation (Smittkamp et al, 2014), it would seem unlikely that altered insulin sensitivity underlies the metabolic changes observed in this study.…”

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

“…Glucose utilization and ATP levels have been shown to be significantly reduced in corticospinal and bulbospinal motor tracts and the motor cortex of SOD1 G93A prior to pathologic changes (Browne et al 2006). Late-stage SOD1 G93A mice also display decreased glucose uptake into skeletal muscle (Smittkamp et al 2014). Furthermore, SOD1 G93A and SOD1 G86R mice show a decrease in body weight and fat mass during disease progression, reduced levels of circulating triglycerides, and evidence of increased lipolysis (Dodge et al 2013, Kim et al 2011a, Fergani et al 2007, Dupuis et al 2004.…”

Dysregulation of microRNA biogenesis machinery and microRNA/RNA ratio in skeletal muscle of amyotrophic lateral sclerosis mice

“…This fiber type pattern mimics alterations in skeletal muscle glucose uptake. Basal non–insulin‐stimulated glucose uptake is increased in fast but not slow muscle in the later stages of disease in SOD1 G93A mice . However, insulin‐stimulated glucose uptake is blunted in both fast and slow muscle at this latter stage.…”

“…Basal noninsulin-stimulated glucose uptake is increased in fast but not slow muscle in the later stages of disease in SOD1 G93A mice. 42 However, insulinstimulated glucose uptake is blunted in both fast and slow muscle at this latter stage. We hypothesize that the increased amount of miRNAs produced in these muscles may constitute a compensatory process in muscle tissue undergoing constant degeneration.…”