Sporadic inclusion-body myositis and hereditary inclusion-body myopathies are progressive muscle diseases leading to severe disability. We briefly summarize their clinical pictures and pathologic diagnostic criteria and discuss the latest advances in illuminating their pathogenic mechanism(s). We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis, including (a) increased transcription and accumulation of amyloid-β precursor protein and accumulation of its proteolytic fragment amyloid-β; (b) abnormal accumulation of components related to lipid metabolism, for example, cholesterol, accumulation of which is possibly owing to its abnormal trafficking; (c) oxidative stress; (d) accumulations of other Alzheimer's disease—related proteins; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss a potentially very important role of unfolded and/or misfolded proteins as a possible mechanism in the formations of the inclusion bodies and other abnormalities. (J Child Neurol 2003;18:185-190) .
Dalakas MC: The molecular and cellular pathology of inflammatory muscle diseases. Curr Opin Pharmacol2001; 1: 300—306.
3.
Mendell J.: New insights, current concepts in the pathophysiology of inflammatory myopathies . Adv Immunotherapy2001; 8: 12—16.
4.
Engel WK, Askanas V.: Treatment of inclusion-body myositis and hereditary inclusion-body myopathy with reference to pathogenic mechanism. Personal experiences, in Askanas V, Serratrice G, Engel WK (eds): Inclusion-Body Myositis and Myopathies. Cambridge, United Kingdom: Cambridge University Press, 1998, 351—382.
5.
Askanas V., Engel WK: Inclusion-body myositis: Newest concepts of pathogenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol2001; 60: 1—14.
6.
Jin LW, Hearn MG, Ogburn CE, et al: Transgenic mice over-expressing the C-99 fragment of betaPP with an alpha-s myopathy similarto human inclusion body myositis. A m J P a t h o l1998;153:1679—1686.
7.
Fukuchi K., Pham D., Hart M., et al: Amyloid-beta deposition in skeletal muscle of transgenic mice: Possible model of inclusion body myopathy. Am J Pathol1998; 153: 1687—1693.
8.
Sugarman MC, Yamasaki TR, Oddo S., et al: Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle. Proc Natl Acad Sci U S A2002;99:8334—8339.
9.
Gallardo E., Rojas-Garcia R., de Luna N., et al: Inflammation in dysferlin myopathy: Immunohistochemical characterization of 13 patients. Neurology2001; 57: 2136—2138.
10.
Di Blasi C, Mora M., Pareyson D., et al: Partial laminin α2 chain deficiency in a patient with myopathy resembling inclusion body myositis. Ann Neurol2000; 47: 811—816.
Askanas V., Engel WK: New advances in inclusion-body myositis. Curr Opin Rheumatol1993;5:732—741.
13.
Askanas V., Engel WK: Hereditary inclusion-body myopathies, in Rosenberg RN, Prusiner SB, DiMauro S, et al (eds): The Molecular and Genetic Basis of Neurologic and Psychiatric Disease, 3rd ed. Philadelphia: Butterworth-Heinemann , in press.
14.
Yunis EJ, Samaha FJ: Inclusion body myositis. Lab Invest1971;25:240—248.
15.
Askanas V., Engel WK: Newest approaches to diagnosis and pathogenesis of sporadic inclusion-body myositis and hereditary inclusion-body myopathies, including molecular-pathologic similarities to Alzheimer disease, in Askanas V, Serratrice G, Engel WK (eds): Inclusion-Body Myositis and Myopathies. Cambridge, United Kingdom: Cambridge University Press, 1998, 3—78.
16.
Askanas V., Engel WK: Late-juvenile sporadic inclusion body myositis: A n e w l y r e c o g n i z e d s y n d r o m e . A n nNeurol2000;48:439—440.
17.
Askanas V., Engel WK, Alvarez RB, et al: Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and transthyretin Vall22lle Allele. Ann Neurol2000; 47: 544—549.
18.
Eisenberg I., Avidan N., Potikha T., et al: The UDP-N-acetylglucosamine 2-epimerase/N acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet2001;29:83—87.
19.
Tomimitsu H., Ishikawa K., Shimizu J., et al: Distal myopathy with rimmed vacuoles: Novel mutations in the GNE gene. Neurology2002;59(Suppl3):451-454.
20.
Arai A., Tanaka K., Ikeuchi T., et al: A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees. Ann Neurol2002; 52: 516—519.
21.
Vasconcelos OM, Raghavan R., Granger R., et al: Detection of two mutant alleles in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE) in a cohort of patients with sporadic and hereditary inclusion body myopathies (IBM). Neurology2002;58(Suppl 3):A390.
22.
Stäschet, Hinderlich S, Weise C., et al: A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. J Biol Chem1997;272:24319—24324.
23.
Lucka L., Krause M., Danker K., et al: Primary structure and expression analysis of human UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, the bifunctional enzyme in neuraminic acid biosynthesis. FEBS Lett1999;454:341—344.
24.
Keppler OT, Hinderlich S., Langner J., et al: UDP-GlcNAc 2-epimerase: A regulator of cell surface sialylation . Science1999;284:1372—1376.
25.
Askanas V., Engel WK, Alvarez RB: Enhanced detection of congo-red positive amyloid deposits in muscle fibers of inclusion-body myositis and brain of Alzheimer disease using fluorescence technique. Neurology1993;43:1265—1267.
26.
Askanas V., Alvarez RB, Mirabella M., et al: Use of antineurofilament antibody to identify paired-helical filaments in inclusion-body myositis. Ann Neurol1996;39:389—391.
27.
Engel WK, Cunningham GG: Rapid examination of muscle tissue— an improved trichrome method for fresh-frozen biopsy sections. Neurology1963 ;13:919—923.
28.
Askanas V., Serdaroglu P., Engel WK, et al: Immunocytochemical localization of ubiquitin in inclusion-body myositis allows its light-microscopic distinction from polymyositis. Neurology1992;42:460—461.
29.
Prayson RA, Cohen ML: Ubiquitin immunostaining and inclusion body myositis: Study of 30 patients with inclusion body myositis. Hum Pathol1997 ;28:887—892.
30.
Alvarez RB, Simmons Z., Engel WK: New autosomal-dominant inclusion-body myopathy (AD-IBM) with many congophilic muscle nuclei that contain paired-helical filaments (PHFs) composed of phosphorylated tau. Neurology1998;50:A204.
31.
Mirabella M. , Alvarez RB, Bilak M., et al: Difference in expression of phosphorylated tau epitopes between sporadic inclusion-body myositis and hereditary inclusion-body myopathies. J Neuropathol Exp Neurol1996; 55: 774—786.
32.
Mirabella M. , Alvarez RB, Engel WK, et al: Apolipoprotein E and apolipoprotein E messenger RNA in muscle of inclusion body myositis and myopathies. Ann Neurol1996;40:864—872.
33.
Askanas V., Alvarez RB, Sarkozi E., et al: Partial expression of oculopharyngeal muscular dystrophy (OPMD) muscle fibers of the intracellular phenotype of sporadic inclusion-body myositis (s-IBM). Neurology1997; 48: A331.
Bucciantini M., Giannoni E., Chiti F., et al: Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature2002;416:507—511.
38.
Sherman MY, Goldberg AL: Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron2001;29:15—32.
39.
Rajan RS, Illing ME, Bence NF, et al: Specificity in intracellular protein aggregation and inclusion body formation. Proc Natl Acad Sci U S A2001 ;98:13060—13065.
40.
Vattemi G., Engel WK, Askanas V.: Evidence of endoplasmic reticulum stress and unfolded protein response in inclusion-body myositis (IBM) muscle. Neurology2002; 58: A491.
41.
Ma Y., Hendershot LM: The unfolding tale of the unfolded protein response. Cell2001; 107: 827—830.
42.
Askanas V., McFerrin J., Baque S., et al. Transfer of β-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle . Proc Natl Acad Sci U S A1996;93:1314—1319.
43.
Askanas V., McFerrin J., Alvarez RB, et al: βAPP gene transfer into cultured human muscle induces inclusion-body myositis aspects. Neuroreport1997;8:2155—2158.
44.
McFerrin J. , Engel WK, Askanas V.: Impaired innervation of cultured human muscle overexpressing βAPP experimentally and genetically: Relevance to inclusion-body myopathies. Neuroreport1998;9:3201—3205.
45.
Mahley RW, Rall SCJr: Type III hyperlipoproteinemia (dysbetalipoproteinemia): The role of apolipoprotein E in normal and abnormal lipoprotein metabolism, in Scriver CR, Beaudet AL, Sly WS (eds): Metabolic and Molecular Bases of Inheritied Diseases, 8th ed. New York, McGraw-Hill, 2001, 2863—2913.
46.
Jaworska-Wilczynska M., Wilczynski GM, Engel WK, et al: Three lipoprotein receptors and cholesterol in inclusion-body myositis muscle. Neurology2002; 58: 438—445.
47.
Kefi M., Vattemi G., Engel WK, et al: Abnormal accumulation of caveolin-1 and its co-localization with cholesterol, amyloid-β and phosphorylated tau in inclusion-body myositis (IBM) muscle. Neurology2002 ;58:A391.
48.
Fielding CJ , Fielding PE: Cholesterol and caveolae: Structural and functional relationships. Biochem Biophys Acta2000;1529:210—222.
