Genetic induction of hypometabolism by ablation of MC4R does not suppress ALS-like phenotypes in the G93A mutant SOD1 mouse model

Abstract

Dysfunction and death of motor neurons leads to progressive paralysis in amyotrophic lateral sclerosis (ALS). Recent studies have reported organism-level metabolic dysfunction as a prominent but poorly understood feature of the disease. ALS patients are hypermetabolic with increased resting energy expenditure, but if and how hypermetabolism contributes to disease pathology is unknown. We asked if decreasing metabolism in the mutant superoxide dismutase 1 (SOD1) mouse model of ALS (G93A SOD1) would alter motor function and survival. To address this, we generated mice with the G93A SOD1 mutation that also lacked the melanocortin-4 receptor (MC4R). MC4R is a critical regulator of energy homeostasis and food intake in the hypothalamus. Loss of MC4R is known to induce hyperphagia and hypometabolism in mice. In the MC4R null background, G93A SOD1 mice become markedly hypometabolic, overweight and less active. Decreased metabolic rate, however, did not reverse any ALS-related disease phenotypes such as motor dysfunction or decreased lifespan. While hypermetabolism remains an intriguing target for intervention in ALS patients and disease models, our data indicate that the melanocortin system is not a good target for manipulation. Investigating other pathways may reveal optimal targets for addressing metabolic dysfunction in ALS.

Repurposing of Trimetazidine for amyotrophic lateral sclerosis: A study in SOD1G93Amice

“…increased metabolic rate) seen in SOD1 G93A mice (Scaricamazza et al, 2020 ; Steyn et al, 2020 ). This is of clinical importance as hypermetabolism is associated with poor outcomes in mouse models of ALS and in human ALS (Doshi et al, 2017 ; Dupuis et al, 2004 ; Fayemendy et al, 2021 ; Jésus et al, 2018 ; Scaricamazza et al, 2020 ; Steyn et al, 2018 ). In 2020, we demonstrated that treatment of SOD1 G93A mice with the metabolic modulator ranolazine was able to improve locomotor function, decrease metabolic rate and partially rescue the dysfunction of muscle metabolism in SOD1 G93A mice (Scaricamazza et al, 2020 ).…”

Energy metabolism in ALS: an underappreciated opportunity?

“…Recently, the melanocortin pathway, a critical regulator of energy homeostasis and food intake in the hypothalamus [ 184 ], was hypothesized to contribute to imbalanced energy homeostasis in ALS patients [ 67 ] and mice [ 201 ]. However, reducing energy expenditure and inducing hyperphagia by targeting this pathway in mutant SOD1 G93A mice did not improve motor function or lifespan [ 53 ]. While the cause and importance of dysregulated energy homeostasis in human ALS remains to be established, body weight loss is an important prognostic factor in patients [ 149 ].…”