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

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

Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, USA.

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.

Keywords

Mitochondrial Dynamics, Autophagy, Mitochondrial Biogenesis, Amyloid Beta Precursor Protein, 5’-AMP-Activated Protein Kinase

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	McBride, H.M., Neuspiel, M. and Wasiak, S. (2006) Mitochondria: More than Just a Powerhouse. Current Biology, 16, R551-R560. http://dx.doi.org/10.1016/j.cub.2006.06.054
[2]	Romanello, V. and Sandri, M. (2010) Mitochondrial Biogenesis and Fragmentation as Regulators of Muscle Protein Degradation. Current Hypertension Reports, 12, 433-439. http://dx.doi.org/10.1007/s11906-010-0157-8
[3]	Boudina, S. and Abel, E.D. (2006) Mitochondrial Uncoupling: A Key Contributor to Reduced Cardiac Efficiency in Diabetes. Physiology, 21, 250-258. http://dx.doi.org/10.1152/physiol.00008.2006
[4]	de Castro, I.P., Martins, L.M. and Tufi, R. (2010) Mitochondrial Quality Control and Neurological Disease: An Emerging Connection. Expert Reviews in Molecular Medicine. http://dx.doi.org/10.1017/S1462399410001456
[5]	Lanza, I.R. and Nair, K.S. (2010) Mitochondrial Function as a Determinant of Life Span. Pflugers Archiv: European Journal of Physiology, 459, 277-289. http://dx.doi.org/10.1007/s00424-009-0724-5
[6]	Berman, S.B., Pineda, F.J. and Hardwick, J.M. (2008) Mitochondrial Fission and Fusion Dynamics: The Long and Short of It. Cell Death and Differentiation, 15, 1147-1152. http://dx.doi.org/10.1038/cdd.2008.57
[7]	Karbowski, M. and Youle, R.J. (2003) Dynamics of Mitochondrial Morphology in Healthy Cells and during Apoptosis. Cell Death and Differentiation, 10, 870-880. http://dx.doi.org/10.1038/sj.cdd.4401260
[8]	Liesa, M., Palacin, M. and Zorzano, A. (2009) Mitochondrial Dynamics in Mammalian Health and Disease. Physiological Reviews, 89, 799-845. http://dx.doi.org/10.1152/physrev.00030.2008
[9]	Chen, H., Vermulst, M., Wang, Y.E., Chomyn, A., Prolla, T.A., McCaffery, J.M., et al. (2010) Mitochondrial Fusion is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA Mutations. Cell, 141, 280-289. http://dx.doi.org/10.1016/j.cell.2010.02.026
[10]	Cipolat, S., Martins de Brito, O., Dal Zilio, B. and Scorrano, L. (2004) OPA1 Requires Mitofusin 1 to Promote Mitochondrial Fusion. Proceedings of the National Academy of Sciences of the United States of America, 101, 15927-15932. http://dx.doi.org/10.1073/pnas.0407043101
[11]	Pitts, K.R., Yoon, Y., Krueger, E.W. and McNiven, M.A. (1999) The Dynamin-Like Protein DLP1 Is Essential for Normal Distribution and Morphology of the Endoplasmic Reticulum and Mitochondria in Mammalian Cells. Molecular Biology of the Cell, 10, 4403-4417.
[12]	Rojo, M., Legros, F., Chateau, D. and Lombes, A. (2002) Membrane Topology and Mitochondrial Targeting of Mitofusins, Ubiquitous Mammalian Homologs of the Transmembrane GTPase Fzo. Journal of Cell Science, 115, 1663-1674.
[13]	Blass, J.P. (2000) The Mitochondrial Spiral. An Adequate Cause of Dementia in the Alzheimer’s Syndrome. Annals of the New York Academy of Sciences, 924, 170-183.
[14]	Cardenas, A.M., Ardiles, A.O., Barraza, N., Baez-Matus, X. and Caviedes, P. (2012) Role of Tau Protein in Neuronal Damage in Alzheimer’s Disease and Down Syndrome. Archives of Medical Research, 43, 645-654. http://dx.doi.org/10.1016/j.arcmed.2012.10.012
[15]	Keller, J.N., Guo, Q., Holtsberg, F.W., Bruce-Keller, A.J. and Mattson, M.P. (1998) Increased Sensitivity to Mitochondrial Toxin-Induced Apoptosis in Neural Cells Expressing Mutant Presenilin-1 Is Linked to Perturbed Calcium Homeostasis and Enhanced Oxyradical Production. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 18, 4439-4450.
[16]	Wang, X., Su, B., Siedlak, S.L., Moreira, P.I., Fujioka, H., Wang, Y., et al. (2008) Amyloid-Beta Overproduction Causes Abnormal Mitochondrial Dynamics via Differential Modulation of Mitochondrial Fission/Fusion Proteins. Proceedings of the National Academy of Sciences of the United States of America, 105, 19318-19323. http://dx.doi.org/10.1073/pnas.0804871105
[17]	Moslemi, A.R., Lindberg, C. and Oldfors, A. (1997) Analysis of Multiple Mitochondrial DNA Deletions in Inclusion Body Myositis. Human Mutation, 10, 381-386. http://dx.doi.org/10.1002/(SICI)1098-1004(1997)10:5<381::AID-HUMU8>3.0.CO;2-I
[18]	Rifai, Z., Welle, S., Kamp, C. and Thornton, C.A. (1995) Ragged Red Fibers in Normal Aging and Inflammatory Myopathy. Annals of Neurology, 37, 24-29. http://dx.doi.org/10.1002/ana.410370107
[19]	Schroder, J.M. and Molna, R.M. (1997) Mitochondrial Abnormalities and Peripheral Neuropathy in Inflammatory Myopathy, Especially Inclusion Body Myositis. Molecular and Cellular Biochemistry, 174, 277-281.
[20]	Boncompagni, S., Moussa, C.E., Levy, E., Pezone, M.J., Lopez, J.R., Protasi, F., et al. (2012) Mitochondrial Dysfunction in Skeletal Muscle of Amyloid Precursor Protein-Overexpressing Mice. The Journal of Biological Chemistry, 287, 20534-20544. http://dx.doi.org/10.1074/jbc.M112.359588
[21]	Oldfors, A., Moslemi, A.R., Jonasson, L., Ohlsson, M., Kollberg, G. and Lindberg, C. (2006) Mitochondrial Abnormalities in Inclusion-Body Myositis. Neurology, 66, S49-S55. http://dx.doi.org/10.1212/01.wnl.0000192127.63013.8d
[22]	Askanas, V., Engel, W.K. and Alvarez, R.B. (1993) Enhanced Detection of Congo-Red-Positive Amyloid Deposits in Muscle Fibers of Inclusion Body Myositis and Brain of Alzheimer’s Disease Using Fluorescence Technique. Neurology, 43, 1265-1267.
[23]	Askanas, V. and Engel. W.K. (2011) Sporadic Inclusion-Body Myositis: Conformational Multifactorial Ageing-Related Degenerative Muscle Disease Associated with Proteasomal and Lysosomal Inhibition, Endoplasmic Reticulum Stress, and Accumulation of Amyloid-Beta42 Oligomers and Phosphorylated Tau. Presse médicale, 40, e219-e235. http://dx.doi.org/10.1016/j.lpm.2010.11.024
[24]	Greenberg, S.A. (2009) Inclusion Body Myositis: Review of Recent Literature. Current Neurology and Neuroscience Reports, 9, 83-89.
[25]	Zhu, X., Perry, G., Moreira, P.I., Aliev, G., Cash, A.D., Hirai, K., et al. (2006) Mitochondrial Abnormalities and Oxidative Imbalance in Alzheimer Disease. Journal of Alzheimer’s Disease, 9, 147-153.
[26]	Cardoso, S.M., Santana, I., Swerdlow, R.H. and Oliveira, C.R. (2004) Mitochondria Dysfunction of Alzheimer’s Disease Cybrids Enhances a Beta Toxicity. Journal of Neurochemistry, 89, 1417-1426.
[27]	Anandatheerthavarada, H.K., Biswas, G., Robin, M.A. and Avadhani, N.G. (2003) Mitochondrial Targeting and a Novel Transmembrane Arrest of Alzheimer’s Amyloid Precursor Protein Impairs Mitochondrial Function in Neuronal Cells. The Journal of Cell Biology, 161, 41-54. http://dx.doi.org/10.1083/jcb.200207030
[28]	Devi, L., Prabhu, B.M., Galati, D.F., Avadhani, N.G. and Anandatheerthavarada, H.K. (2006) Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction. The Journal of Neuroscience, 26, 9057-9068. http://dx.doi.org/10.1523/JNEUROSCI.1469-06.2006
[29]	Mancuso, M., Orsucci, D., LoGerfo, A., Calsolaro, V. and Siciliano, G. (2010) Clinical Features and Pathogenesis of Alzheimer’s Disease: Involvement of Mitochondria and Mitochondrial DNA. Advances in Experimental Medicine and Biology, 685, 34-44.
[30]	Mark, R.J., Pang, Z., Geddes, J.W., Uchida, K. and Mattson, M.P. (1997) Amyloid Beta-Peptide Impairs Glucose Transport in Hippocampal and Cortical Neurons: Involvement of Membrane Lipid Peroxidation. The Journal of Neuroscience, 17, 1046-1054.
[31]	Frisard, M.I., McMillan, R.P., Marchand, J., Wahlberg, K.A., Wu, Y., Voelker, K.A., et al. (2010) Toll-Like Receptor 4 Modulates Skeletal Muscle Substrate Metabolism. American Journal of physiology Endocrinology and Metabolism, 298, E988-E998. http://dx.doi.org/10.1152/ajpendo.00307.2009
[32]	Hulver, M.W., Berggren, J.R., Carper, M.J., Miyazaki, M., Ntambi, J.M., Hoffman, E.P., et al. (2005) Elevated Stearoyl-CoA Desaturase-1 Expression in Skeletal Muscle Contributes to Abnormal Fatty Acid Partitioning in Obese Humans. Cell Metabolism, 2, 251-261. http://dx.doi.org/10.1016/j.cmet.2005.09.002
[33]	Twig, G., Hyde, B. and Shirihai, O.S. (2008) Mitochondrial Fusion, Fission and Autophagy as a Quality Control Axis: The Bioenergetic View. Biochimica et Biophysica Acta, 1777, 1092-1097.
[34]	Busch, K.B., Bereiter-Hahn, J., Wittig, I., Schagger, H. and Jendrach, M. (2006) Mitochondrial Dynamics Generate Equal Distribution but Patchwork Localization of Respiratory Complex I. Molecular Membrane Biology, 23, 509-520. http://dx.doi.org/10.1080/09687860600877292
[35]	Wikstrom, J.D., Twig, G. and Shirihai, O.S. (2009) What Can Mitochondrial Heterogeneity Tell Us about Mitochondrial Dynamics and Autophagy? The International Journal of Biochemistry & Cell Biology, 41, 1914-1927. http://dx.doi.org/10.1016/j.biocel.2009.06.006
[36]	McGee, S.L. and Hargreaves, M. (2004) Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle. Diabetes, 53, 1208-1214.
[37]	Watt, M.J., Southgate, R.J., Holmes, A.G. and Febbraio, M.A. (2004) Suppression of Plasma Free Fatty Acids Upregulates Peroxisome Proliferator-Activated Receptor (PPAR) Alpha and Delta and PPAR Coactivator 1α in Human Skeletal Muscle, but Not Lipid Regulatory Genes. Journal of Molecular Endocrinology, 33, 533-544. http://dx.doi.org/10.1677/jme.1.01499
[38]	Romanello, V. and Sandri, M. (2013) Mitochondrial Biogenesis and Fragmentation as Regulators of Protein Degradation in Striated Muscles. Journal of Molecular and Cellular Cardiology, 55, 64-72. http://dx.doi.org/10.1016/j.yjmcc.2012.08.001
[39]	Sarkozi, E., Askanas, V., Johnson, S.A., Engel, W.K. and Alvarez, R.B. (1993) Beta-Amyloid Precursor Protein m-RNA Is Increased in Inclusion-Body Myositis Muscle. Neuroreport, 4, 815-818. http://dx.doi.org/10.1097/00001756-199306000-00055
[40]	Garcia-Roves, P.M., Osler, M.E., Holmstrom, M.H. and Zierath, J.R. (2008) Gain-of-Function R225Q Mutation in AMP-Activated Protein Kinase Gamma3 Subunit Increases Mitochondrial Biogenesis in Glycolytic Skeletal Muscle. The Journal of Biological Chemistry, 283, 35724-35734. http://dx.doi.org/10.1074/jbc.M805078200
[41]	Shull, S., Heintz, N.H., Periasamy, M., Manohar, M., Janssen, Y.M., Marsh, J.P., et al. (1991) Differential Regulation of Antioxidant Enzymes in Response to Oxidants. The Journal of Biological Chemistry, 266, 24398-24403.
[42]	Warner, B.B., Stuart, L., Gebb, S. and Wispe, J.R. (1996) Redox Regulation of Manganese Superoxide Dismutase. The American Journal of Physiology, 271, L150-L158.
[43]	Benard, G., Bellance, N., James, D., Parrone, P., Fernandez, H., Letellier, T., et al. (2007) Mitochondrial Bioenergetics and Structural Network Organization. Journal of Cell Science, 120, 838-848. http://dx.doi.org/10.1242/jcs.03381
[44]	Distelmaier, F., Valsecchi, F., Forkink, M., van Emst-de Vries, S., Swarts, H.G., Rodenburg, R.J., et al. (2012) Trolox-Sensitive Reactive Oxygen Species Regulate Mitochondrial Morphology, Oxidative Phosphorylation and Cytosolic Calcium Handling in Healthy Cells. Antioxidants & Redox Signaling, 17, 1657-1669. http://dx.doi.org/10.1089/ars.2011.4294
[45]	Mastaglia, F.L. (2009) Sporadic Inclusion Body Myositis: Variability in Prevalence and Phenotype and Influence of the MHC. Acta Myologica, 28, 66-71.