Effects of diet on adenosine monophosphate-activated protein kinase activity and disease progression in an amyotrophic lateral sclerosis model

Abstract

Objectives: To study the effects of diet on disease progression and activity levels of adenosine monophosphate-activated protein kinase (AMPK), and its downstream targets, in an amyotrophic lateral sclerosis (ALS) animal model.

Methods: AMPK activity was measured in cerebral cortex, spinal cord, cerebellum and hindlimb muscle tissue using immunohistochemistry in transgenic mice overexpressing human superoxide dismutase-1 (SOD1(G93A)) fed a high-fat (HFD), standard ad libitum (AL) or calorie-restricted (CR) diet; AMPK activity was also measured in wild-type (SOD1(WT)) mice. Activity of AMPK and phospho-AMPK, acetyl coenzyme-A carboxylase (ACC), phospho-ACC and heat shock protein-70 (Hsp70) were also measured using Western blot. Food intake and grip strength were recorded; body composition was analysed using dual energy X-ray absorptiometry. Motor neuron survival was observed using Nissl staining.

Results: AMPK activity increased and Hsp70 expression decreased in AL SOD1(G93A) mice compared with SOD1(WT) mice in spinal cord and hindlimb muscle. Compared with AL SOD1(G93A) mice, CR SOD1(G93A) mice showed increased AMPK activity, downregulated Hsp70 expression, reduced motor neuron survival in spinal cord and hindlimb muscle and reduced lifespan; HFD SOD1(G93A) mice showed opposite effects.

Conclusions: In this mouse model, increased AMPK activity seems to play a negative role in motor neuron survival, possibly through a novel mechanism involving Hsp70 downregulation. These changes can be modified by diet. Inhibition of AMPK may provide a therapeutic strategy for ALS.

Keywords: Amyotrophic lateral sclerosis; adenosine monophosphate-activated protein kinase; calorie restriction; heat shock protein-70; high-fat diet; metabolism.