Tubular aggregates: their association with myalgia

Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:882-886

Tubular aggregates: their association with myalgia

ENAYAT NIAKAN,* YADOLLAH HARATI,* MORIS J DANONt

From the Department ofNeurology, Baylor College of Medicine, Houston * and Department ofNeurologytUniversity of Illinois Medical Center, Chicago, USA

SUMMARY Three thousand consecutive muscle biopsies were reviewed for the presence of tubularaggregates and their association with clinical symptomatology. Tubular aggregates were detectedin 19 patients (0.6%). Twelve of these nineteen patients had severe myalgia, and the most

abundant tubular aggregates were found in biopsies of patients with myalgia. Seven patients hadonly myalgia as their clinical symptomatology with normal physical examination. An additionalfive patients with tubular aggregates and myalgia had concomitant amyotrophic lateral sclerosis(2) or neuropathy (3). The high incidence of myalgia associated with tubular aggregates in our

patients and the fact that tubular aggregates originate from sarcoplasmic reticulum suggest a roleplayed by this structure in the pathogenesis of myalgia.

Tubular aggregates are visible by light microscopywithin Type II muscle fibres as a mass in the subsar-colemmal region with strong NADH-tetrazoliumreductase (NADH-TR) and negative succinicdehydrogenase reactions. Ultrastructurally they areclosely packed, parallel, double-walled tubuleswhich appear to be a proliferation of sarcoplasmicreticulum.' The diagnostic importance of tubularaggregates is uncertain because they are present inmuscles of patients with a wide variety of disor-ders.' -21 Recently tubular aggregates have beendescribed in muscle biopsy specimens of patientswith myalgia who are otherwise normal.2'26 Thefact that tubular aggregates originates from sarco-plasmic reticulum, which has an important role inregulation of muscle contracture and relaxation,suggests a relationship between tubular aggregates,sarcoplasmic reticulum and myalgia. To clarify thisrelationship, we reviewed muscle biopsy specimensfor the presence of tubular aggregates and theirassociation with clinical symptomatology.

Methods

We analysed all 3000 muscle biopsy specimens at ourinstitution in the preceeding seven years. All were from the

Presented in part at the Thirty-Sixth Annual Meeting of theAmerican Academy of Neurology, Boston, April, 1984

Address for reprint requests: Dr Harati, Department of Neurology,Baylor College of Medicine, 6501 Fannin, Houston, Texas 77030,USA.

Received 5 June 1984 and in revised form 27 August 1984Accepted 1 September 1984

quadriceps or biceps muscles. For histochemical studies,tissue had been frozen with liquid nitrogen, sectionedat 10,1L in a cryostat, and stained with the followingmethods: Modified Gomori Trichrome (TRI), NADH-TR,adenosine triphosphatase (ATPase) at pH 9-4, succinicdehydrogenase and phosphorylase. For electon micros-copy, tissue had been fixed in 1% glutaraldehyde bufferedat pH 7-4 for 11/2 h and then fixed in 1% osmium tetroxidefor another hour. Some material was then embedded inEpon and sections 1 ,u thick were cut for all blocks, stainedwith toluidine blue and examined under the light micros-copy. Thin sections for electron microscopy were thenstained with uranyl acetate and with lead citrate.

Results

Among 3000 patients 19 (0.6%) had histochemi-cally typical tubular aggregates; 17 patients weremale and two female. With the TRI stain, the tubu-lar aggregates appeared as bright red staining sub-sarcolemmal material. Tubular aggregates were seenonly in the Type II fibres, were darkly stained by theNADH-TR, and unstained by ATPase and succi-nate dehydrogenase (fig 1). Further studies includ-ing electron microscope and epoxy resin histologywere done in some cases which showed closelypacked, parallel, double-walled tubules (fig 2).

Five biopsies showed less than 1% fibres affectedwith tubular aggregates, six between 1-10%, andeight had more than 10% fibres with tubular aggre-gates. This was determined after obtaining a 10OXphotograph of each biopsy specimen and countingthe number of tubular aggregates per 200 musclefibres.

Clinically, 12 of 19 patients had severe myalgia,882

Tubular aggregates: their association with myalgia

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and the most abundant tubular aggregates werefound in specimens from these patients. Sevenpatients had only myalgia as their clinical symp-tomatology with normal physical examination andlaboratory tests. Three of them had muscle tender-ness on palpation. Tubular aggregates was the pre-dominant abnormality in the muscle of thesepatients. Two patients with tubular aggregates andmyalgia had amyotrophic lateral sclerosis and threehad peripheral neuropathy. The seven remainingcases who did not have myalgia had neuropathy(two) amyotrophic lateral sclerosis (one), systemiclupus erythematosis (one), congenital myopathy(one), and two of the patients had muscle weaknesswith undetermined aetiology. No patient had tubu-lar aggregates associated with drug use.

Discussion

Tubular aggregates are distinguished from raggedred fibres on the basis of strong NADH-TR andnegative succinate dehydrogenase reactions andbecause tubular aggregates only affect Type II

fibres. The differential diagnosis of tubular aggre-gates include other tubular structures within musclefibres.'2 16 Honeycomb structures are round emptyspaces in an hexagonal arrangement that can resem-

ble tubular aggregates. Tubular aggregates shouldalso be differentiated from cylindrical spirals, whichhave also been reported in patients with differentclinical presentations." 27-29 Histochemically, theappearance of cylindrical spirals is similar to tubularaggregates.'" 27 29 They also affect Type II fibresexclusively, but their unique electron microscopicappearances differentiate them from tubular aggre-gates.'" 27-29 They may, however, be associated withtubular aggregates.'" 27 The origin and significance ofcylindrical spirals are uncertain.

Tubular aggregates have been reported in a

wide variety of disorders including alcoholicmyopathy,'6 '7 gyrate atrophy of the eye,2 con-genital myasthenia gravis,4-I 14 myotonia,7hypokalaemic periodic paralysis,' 8 9 18-21 hyper-kalaemic periodic paralysis,' normokalaemicperiodic paralysis,'3 inflammatory myopathy,2'diabetic amyotrophy,3 hyperaldosteronism,'2

884 Niakan, Harati, Danon

Tubular aggregates: their association with myalgia

prophyria cutanea tarda' and chronic drug expos-ure.' A similar abnormality has been found in mus-cles of mice after anoxia30 and after local injection ofbotulinum,3' tetanus toxin,3' and perhexiline male-ate33 and in murine dystrophic heterozygotes.34Tubular aggregates have also been described inassociation with myalgia in otherwise normal indi-viduals.226 Twelve of 19 of our patients with tubu-lar aggregates had severe myalgia. Seven patientshad myalgia as their sole clinical symptomatologyand despite extensive investigation, no definitediagnosis could be made. Like patients reported byRosenberg et al,2' myalgia was not necessarily pre-cipitated by exercise. Three of these cases hadsevere muscle tenderness on palpation. Tubularaggregates was the prominent abnormality in themuscle of these patients. Five other patients withtubular aggregates and myalgia had concomitantamyotrophic lateral sclerosis or neuropathy. In thesepatients myalgia was one of their major complaints.

It is generally accepted that tubular aggregatesoriginate in the sarcoplasmic reticulum, but theirpathogenesis is unknown. Based on the finding oftubular aggregates in muscle biopsies of patientschronically using large amounts of analgesic-narcotic drugs and alcohol,' 16 it has been postulatedthat they may form in response to exogenous orendogenous toxin. However, these reports failed toindicate why these medications were taken or whythe muscle biopsies were performed,' 16 and it maybe that the reason for chronic analgesic use was forrelief of myalgia.'6 It has also been suggested thattubular aggregates may represent adaptive hyper-plastic sarcoplasmic reticulum derivatives toimprove calcium uptake in alcoholic myopathy.'7However, there was no history of chronic drug useor alcoholic abuse in our cases. We also doubt thatthis is a virus-induced lesion as postulated byDunkle et al'8 and Bergman,89 since no evidence ofviral infection of muscle was seen. There is thus nosatisfactory explanation for the formation of tubularaggregates, nor for their occurrence in a wide varietyof diseases, but there may be an explanation of thehigh incidence of myalgia associated with them.

Sarcoplasmic reticulum has an important role incontraction and relaxation of muscle. The functionof the sarcoplasmic reticulum is regulation of thecalcium concentration in the vicinity of actin andmyosin interaction. This regulation of calcium con-centration is the control factor for turning on and offthe basic contractile unit, the sarcomere. It is wellknown that malfunction of sarcoplasmic reticuluminterferes with normal contraction and relaxation,and it may cause myalgia. The fact that tubularaggregates originates from sarcoplasmic reticulumand the high incidence of myalgia associated with

885

tubular aggregates in our patients and previousreports of similar cases,2'-26 suggest a role played bythis structure in the pathogenesis of myalgia. Therelationship between tubular aggregates, sarco-plasmic reticulum and calcium metabolism may alsoexplain why tubular aggregates are seen only in theType II fibres. Type II fibres have considerably moresarcoplasmic reticulum than the Type I fibres.35 InType II fibres, the sarcoplasmic reticulum is possiblyqualitatively different from that of the Type 1 fibre.'Also it has been shown in rabbits that white musclefibres (Type II) have more active calcium-concentrating microsoms than red muscle fibres(Type 1).36 These structural differences may predis-pose Type II fibres to tubular aggregates formation.

In spite of relationships between tubular aggre-gates, sarcoplasmic reticulum and myalgia, tubularaggregates are not always associated with myalgia.There may be different types of tubular aggre-gates,'2 16 7 37 38 but there are classic forms of tubularaggregates in patients who never complain of myal-gia. Also, in our patients who had electron micros-copic studies, the pattern of tubular aggregates wassimilar in cases with or without myalgia. Degree ofmuscle fibre involvement with tubular aggregatesmay be an important factor for appearance of myal-gia since the most abundant tubular aggregates werefound in our patients with myalgia.Based on our observation and review of litera-

tures, we suggest the association of myalgia andtubular aggregates may be important. Althoughmyalgia is the most prominent feature in the symp-tomatology of a wide variety of conditions, in manypatients no firm diagnosis can be made despiteextensive investigation.39 Therefore, the presence oftubular aggregates in patients complaining of mayl-gia may be a hallmark and should not be regarded asa nonspecific finding. Recognition of these combina-tions in time may lead to a better understanding ofthe significance of tubular aggregates. This relation-ship between tubular aggregates, sarcoplasmicreticulum and myalgia may also have importanttherapeutic implications, since drugs which areknown to affect these structures may prove benefi-cial in alleviating symptoms of myalgia.

We thank Mr Karam Matta, and Ms C Zultner, forthe technical assistance. Supported in part by a grantfrom the Frost Foundation.

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