Mitochondrial Dysregulation in Skeletal Muscle from Patients Diagnosed with Alzheimer’s Disease and Sporadic Inclusion Body Myositis

Elika Shabrokh,Madlyn Frisard,Ryan Mcmillan,Matt Hulver,Josh Pittman,John Kavanaugh

doi:10.4236/ojmip.2014.42002

Abstract

Mitochondrial dysfunction is implicated in Alzheimer’s disease (AD) and disruption of mitochondrial dynamic pathways has been documented in brains from patients diagnosed with AD; although it is unclear whether other tissues are also affected. Much less is known about the mitochondria in patients diagnosed with sporadic Inclusion Body Myositis (sIBM). The current study examined mitochondrial biology in skeletal muscle from AD and sIBM patients compared to healthy, elderly individuals. Skeletal muscle samples were obtained from the National Disease Research Interchange and mRNA, protein content, and enzyme activity was used to assess mitochondrial parameters. Patients diagnosed with AD or sIBM demonstrated reduced mitofusin 2 and optic atrophy protein 1 protein. AD patients also displayed increased mRNA of superoxide dismutase 2, catalase, and uncoupling protein 3. Amyloid b precursor protein mRNA was higher in sIBM patients only compared to both AD patients and elderly individuals. Both total and phosphorylated AMPK protein content, an upstream regulator of mitochondrial dynamics and biogenesis, were also reduced in sIBM patients. The current study demonstrates a disruption in signaling pathways regulating mitochondrial dynamics in both AD and sIBM patients, although the underlying causes may differ.

Highlights

Mitochondria are dynamic organelles that play a pivotal role in cellular function, as a major site of ATP production, and as an organelle regulating energy metabolism, protein turnover, cellular proliferation, and apoptosis [1] [2]
The purpose of the current paper was to examine pathways regulating mitochondrial fusion and fission as well as regulators of mitochondrial biogenesis and autophagy in skeletal muscle from patients diagnosed with Alzheimer’s disease (AD) and sporadic Inclusion Body Myositis (sIBM) compared with healthy, elderly individuals
While there were no significant differences in uncoupling protein 3 (UCP3) concentrations between sIBM patients and controls, there were trends for higher and lower catalase and SOD2 mRNA, respectively

Summary

Introduction

Mitochondria are dynamic organelles that play a pivotal role in cellular function, as a major site of ATP production, and as an organelle regulating energy metabolism, protein turnover, cellular proliferation, and apoptosis [1] [2]. Mitochondrial function is dependent on a number of factors including mitochondrial biogenesis, mitochondrial autophagy, and dynamics [6] [7]. Mitochondrial dynamics is a concept that includes mitochondrial movement within the cell and mitochondrial interactions controlled by fusion/fission events [8]. The importance of these events has recently become evident with the identification of genes responsible for fusion (mitofusin 1 and 2, optic atrophy protein 1) and fission (dynamin Related Protein 1 and fission 1) [9]-[12]. Pharmacologic and/or genetic manipulation of these genes can result in gross mitochondrial abnormalities including, altered substrate metabolism, reduced oxygen consumption, a decline in ATP synthesis, and mtDNA nucleotide dyshomeostasis [8]. Impairment in mitochondrial function is detrimental to myofiber health and can result in fiber death and muscle atrophy [2]

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