Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.

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

“…This is in accordance with a previously published study that documented increased AMPK activation at PND 90 in these mice (Lim et al 2012, Perera et al 2014. These data may mechanistically link AMPK activation with previously published bioenergetic abnormalities described in this mouse model (Dodge et al 2013, Kim et al 2011a, Fergani et al 2007, Dupuis et al 2004.…”

“…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. ALS patients also exhibit higher resting levels of energy expenditure, weight loss, a hypermetabolic phenotype and increased lipolysis (Kasarskis et al 1996, Desport et al 2005, Dupuis et al 2008, Bouteloup et al 2009, Funalot et al 2009, Dodge et al 2013.…”

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…S4). Motor neuron loss was similar in this mixed background as in previous studies in the original FVB/N background [20,19]. However, Htr2b ablation in SOD1(G86R) mice triggered atrophy of motoneuron cell bodies that was not present in SOD1(G86R); Htr2b +/+ mice (Fig.…”

Sodium Valproate Exerts Neuroprotective EffectsIn Vivothrough CREB-Binding Protein-Dependent Mechanisms But Does Not Improve Survival in an Amyotrophic Lateral Sclerosis Mouse Model

“…Nevertheless, retraction of motor axon from synaptic connection to muscle and fragmentation of the neuromuscular junction are detected before any MN death, suggesting that ALS could be seen as a "dying-back" axonopathy (Fischer et al, 2004;Jokic et al, 2006). We have also shown that muscular metabolic defects and mitochondrial dysfunctions were early symptoms of the pathology (Dupuis et al, 2003(Dupuis et al, , 2004. Furthermore, this idea that MN death could be dissociated from motor dysfunction has been recently strengthened by a study in which MN death was genetically prevented by Bax deletion (Gould et al, 2006).…”