Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1 ^G93A Mice Predates Disease Onset and Is A Promising Therapeutic Target

Summary

Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1 ^G93A mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1 ^G93A mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1 ^G93A mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.

Graphical Abstract

Highlights

• •

  Metabolic switch use occurs early in the skeletal muscle of SOD1 ^G93A mice

• •

  Mitochondrial impairment precedes locomotor deficits and evokes catabolic pathways

• •

  Sarcolipin upregulation in presymptomatic SOD1 ^G93A mice precedes hypermetabolism

• •

  Pharmacological modulation of hypermetabolism improves locomotor performance

Abstract

Drugs; Molecular Neuroscience; Cellular Neuroscience