Abstract
Zidovudine-induced myopathy is characterized by reversible muscle weakness, wasting, myalgia, fatigue, and elevated creatine kinase (CK). Some zidovudine-treated patients with normal muscle strength experience excessive fatigue, myalgia, or transient mild CK elevations that improve when zidovudine is stopped. To determine the cause of these symptoms, we studied 13 physically fit, HIV-infected men who developed fatigue, myalgia, and reduced endurance, while taking zidovudine for a mean period of 20 months (2–39 months), with neurological evaluation and muscle biopsy processed for enzyme histochemistry and electron microscopy (EM). All subjects had normal muscle strength. In 6 of the 13 patients, muscle biopsies were normal by enzyme histochemistry. EM, however, demonstrated proliferation of normal or abnormal mitochondria, and increased amounts of lipid, glycogen, and lipofuscin. Electromyographic (EMG) studies (5/5) and serum CK (6/6) were normal. The other 7 individuals had signs of moderate to severe mitochondrial abnormalities shown by both light microscopy and EM, characterized by severe destruction, vacuolization, and rare paracrystalline inclusions. Most had elevated CK (4 out of 7) and normal EMG (5 out of 7). The severity of morphological abnormalities did not correlate with duration of HIV infection, zidovudine therapy, or zidovudine dosage. We conclude that in zidovudine-treated patients, symptoms of fatigue, myalgia, reduced endurance, and exercise intolerance represent early signs of zidovuline-induced mitochondriotoxicity, which causes an energy shortage within the muscle fibers even when muscle strength is still normal. Zidovudine, a DNA chain terminator, results in overt myopathy when a critical threshold of molecular, histological, and biochemical dysfunction of mitochondria is crossed, which seems to vary between individuals.
Similar content being viewed by others
References
Arnaudo E, Dalakas MC, Shanske S, Moraes C, DiMauro S, Schon E (1991) Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 337: 508–510
Attardi G, Schatz G (1988) Biogenesis of mitochondria. Annu Rev Cell Biol 4: 289–333
Carpenter S, Karpati G (1984) Pathology of skeletal muscle. Churchill Livingstone, New York
Chariot P, Gherardi R (1991) Partial cytochrome c oxidase deficiency and cytoplasmic bodies in patients with zidovudine myopathy. Neuromuscul Disord 5: 357–363
Chariot P, Benbrik E, Schaeffer A, Gherardi R (1993) Tubular aggregates and partial cytochrome c oxidase deficiency in skeletal muscle of patients with AIDS treated with zidovudine. Acta Neuropathol 85: 431–436
Chariot P, Monnet I, Gherardi RK (1993) Cytochrome c oxidase reaction improves histopathologic assessment of zidovudine myopathy. Ann Neurol 34: 561–565
Chen C, Vazquez-Padua M, Cheng Y (1991) Effect of anti-human immunodeficiency virus nucleoside analogues on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 39: 625–628
Dalakas MC (1994) Retroviral myopathies. In: Engel AG, Franzini-Armstrong C (eds) Myology, vol II. McGraw Hill, New York, pp 1413–1437
Dalakas MC (1994) HIV or zidovudine myopathy? (letter). Neurology 44: 360–3611
Dalakas MC, Illa I, Pezeshkpour G, Laukaitis J, Cohen B, Griffin J (1990) Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322: 1098–1105
Dalakas MC, Leon-Monzon M, Bernadini I, Gahl WA, Jay CA (1994) The AZT-induced mitochondrial myopathy associated with muscle carnitine deficiency. Ann Neurol 35: 482–487
Engel AG (1994) The muscle biopsy. In: Engel AG, Franzini-Armstrong C (eds) Myology, vol I. McGraw-Hill, New York, pp 822–831
Gherardi RK (1994) Skeletal muscle involvement in HIV-infected patients. Neuropathol Appl Neurobiol 20: 232–237
Gherardi RK, Goebel HH (1993) Involvement of skeletal muscle. In: Gray F (ed) Atlas of the neuropathology of HIV infection. Oxford University Press, Oxford, pp 261–283
Grau JM, Masanés F, Pedrol E, et al (1993) Human immunod-eficiency virus type 1 infection and myopathy: clinical relevance of zidovuline therapy. Ann Neurol 34: 206–211
Jay C, Ropka M, Hench K, Grady C, Dalakas M (1992) Prospective study of myopathy during prolonged low-dose AZT: clinical correlates of AZT mitochondrial myopathy (AZT-MM) and HIV-associated inflammatory myopathy (HIV-IM). Neurology 42 [Suppl]: 145
Lamperth L, Dalakas MC, Dagani F, Anderson J, Ferrari R (1991) Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model. Lab Invest 65: 742–751
Lewis W, Gonzelez B, Chomyn A, Papoian T (1992) Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria. J Clin Invest 89: 1354–1360
Mhiri C, Baudrimont M, Bonne G, Geny C, Degoul F, Marsac C, Roullet E, Gherardi R (1991) Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol 29: 606–614
Modica-Napolitano JS (1993) AZT causes tissue-specific inhibition of mitochondrial bioenergetic function. Biochem Biophys Res Commun 194: 170–177
Panegyres P, Papadimitriou J, Hollingsworth P, Armstrong J, Kakulas B (1990) Vesicular changes in the myopathies of AIDS. Ultrastructural observations and their relationship to zidovudine treatment. J Neurol Neurosurg Psychiatry 53: 649–655
Peters BS, Winer J, Landon DN, Stoffer A, Pinching AJ (1993) Mitochondrial myopathy associated with chronic zidovudine therapy in AIDS. Q J Med 86: 5–15
Pezeshkpour G, Illa I, Dalakas MC (1991) Ultrastructural characteristics and DNA immunocytochemistry in human immunodeficiency virus and zidovudine-associated myopathy. Hum Pathol 22: 1281–1288
Schroder JM, Bertram M, Schnabel R, Pfaff U (1992) Nuclear and mitochondrial changes of muscle fibers in AIDS after high doses of zidovudine. Acta Neuropathol 85: 39–47
Simpson DM, Citak KA, Godfrey E, Godbold J, Wolfe DE (1993) Myopathies associated with human immunodeficiency virus and zidovudine: can their effects be distinguished? Neurology 43: 971–976
Simpson MV, Chin CD, Keilbough SA, Lin T-S, Prusoff WH (1989) Studies on the inhibition of mitochondrial DNA replication of 3′-azido-3′-deoxythymidine and other dideoxynucleoside analogs which inhibit HIV-1 replication. Biochem Pharmacol 38: 1033–1036
Soueidan S, Sinnwell T, Jay C, Frank J, McLaughlin A, Dalakas M (1992) Impaired muscle energy metabolism in patients with AZT-myopathy: a blinded comparative study of exercise 31P magnetic resonance spectroscopy (MRS) with muscle biopsy (abstract). Neurology 42 [Suppl 3]: 146
Tomelleri G, Tonin P, Spadaro M, et al (1992) AZT-induced mitochondrial myopathy. Ital J Neurol Sci 13: 723–728
Weissman JD, Constantinitis I, Hudgins P, Wallace DC (1992) 31P magnetic resonance spectroscopy suggests impaired mitochondrial function in AZT-treated HIV-infected patients. Neurology 42: 619–623
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cupler, E.J., Jay, C., Dalakas, M.C. et al. Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations. Acta Neuropathol 90, 1–6 (1995). https://doi.org/10.1007/BF00294452
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00294452