Eur Respir J REVIEW 1992, 5, 997-1003

Steroid-induced myopathy and its significance to respiratory disease: a known disease rediscovered

P.N.R. Dekhuijzen, M. Decramer

Steroid-induced myopathy and its significance to respiratory disease: a known dis­ Respiratory Muscle Research Unit, ease rediscovered. P.N.R. Dekhuijzen, M. Decramer. Laboratory for Pneumology and Respi­ ABSTRACT: Skeletal muscle myopathy is a well-known side-effect of systemi­ ratory Division, University Hospital, cally administered corticosteroids. In recent years renewed attention is being Katholieke Universiteit Leuven, B-3000 Leuvcn, Belgium. paid to the involvement of the respiratory muscles and its consequent signifi­ cance in pulmonary patients. Two different clinical patterns of steroid-induced Correspondence: M. Decramer, Respira­ muscular changes are known. In acute myopathy and atrophy after short term tory Division, University Hospital, treatment with high doses of steroids, generalized muscle atrophy and Weligerveld I, 3212 Pellenberg, Bel­ rhabdomyolysis occur, including the respiratory muscles. Chronic steroid my­ gium opathy, occurring after prolonged treatment with moderate doses, is character­ ized by the gradual onset of proximal limb muscle weakness and may be Keywords: Atrophy accompanied by reduced respiratory muscle force. corticosteroids Animal studies demonstrated diaphragmatic myopathy and atrophy similar myopathy respiratory muscles to the alterations in peripheral skeletal muscles. Fluorinated steroids induced selective type lib (fast-twitch glycolytic) fibre atrophy, resulting in changes in Received: January 20 1992 contractile properties of the diaphragm. Non-fluorinated steroids may also Accepted for publication May 7 1992 induce histological, biochemical and functional alterations in the diaphragm. Observations in patients with collagen vascular disorders and with asthma and This study was supported by grants from chronic obstructive pulmonary disease (COPD) underline the potential hazards the Dutch Asthma Foundation and the of treatment with corticosteroids to respiratory muscle structure and function. "Nationaal Fonds voor Wetenschappelijk Eur Respir J, 1992, 5, 997-1003. Onder:wek".

Intravenous and oral corticosteroids are often used function is already affected by hyperinflation, hypox­ in the treatment of obstructive pulmonary disease, aemia, hypercapnia and malnutrition. Moreover, a interstitial lung disease and collagen vascular disorders. reduced average activity level of these patients will Among the many side-effects are myopathy and atro­ lead to the development of disuse atrophy. phy, affecting striated muscles of the limbs. This In the present review, literature on corticosteroid­ occurs primarily when fluorinated steroids such as induced pathological and physiological changes in res­ triamcinolone and dexamethasone are used [1-3]. piratory muscles will be discussed, as well as their In patients, proximal muscle wasting and weakness potential clinical relevance and implications for predominate the clinical picture. Biopsy studies of therapy. peripheral muscles in humans and animals show selective atrophy of the type Ub (fast-twitch glycolytic) fibres [3- 7]. Due to their continuous activity the res­ Clinical picture of steroid-induced myopathy piratory muscles, especially the diaphragm, were thought to be relatively spared by this process. Two distinct types of steroid-induced myopathy are In recent years, however, several studies in animals well-known to the clinician: acute and chronic steroid have shown that diaphragmatic structure and func­ myopathy. tion may be severely compromised by the use of sys­ temic steroids l8-12). Diaphragmatic atrophy and weakness were the main findings in these animal Acute steroid myopathy studies. The extent to which diaphragmatic function may be This complication of treatment with systemic compromised by steroid administration in patients is corticosteroids is infrequently encountered [16-20]. not fully understood [13- 15]. The clinical implications Generalized muscle weakness, involving the respiratory of these changes, however, may be potentially serious muscles, occurs 5-7 days after the onset of treatment in patients with chronic obstructive pulmonary disease with high doses of corticosteroids (e.g. hydrocortisone (COPD) and asthma. In these patients, diaphragmatic 0.9-4 g·day·1 i.v, dexamethasone 40-80 mg·day-1 i.v. 998 P.N.R. DEKHUIJZEN, M. DECRAMER

[ 19]). In one study [20], there appeared to be a The distribution of the different fibre types, however, correlation between the occurrence of this complication was not changed [7, 23, 24). Recovery of weakness and the total dose of steroids administered. Acute associated with chronic use of steroids may take many atrophy was encountered with total doses >5.4 g of weeks or months [25]. hydrocortisone in six days, whereas no signs of my­ Corticosteroids preferentially affect less active mus­ opathy were noted with total doses <4 g [20]. cles [26]. Moreover, muscles with predominantly type In most cases, high levels of creatine kinase were Jib fibres are especially susceptible to steroid-induced 1 found (1,000-100,000 U·/· ), associated to myoglobinu­ wasting [27, 28]. In this respect the almost continu­ ria, indicating rhabdomyolysis. Muscle biopsies show ously active diaphragm, mainly composed of type I focal and diffuse necrosis and atrophy of all fibre and Ha fibres, would not be expected to be affected types [17, 19], without predilection for type lib fibres. by corticosteroids. Recent animal studies, however, Previous use of systemic corticosteroids was apparently have cast doubt on this expectation. not involved in the development of this rare compli­ cation of steroid therapy. Recovery may be prolonged to more than six months [ 19]. Respiratory muscle involvement in animal studies

Chronic steroid myopathy The effects of steroids on physiological, histochem­ ical and biochemical characteristics of the diaphragm This is the classical type of steroid-induced myopa­ have been described in several animal studies. The thy, occurring after prolonged administration of pred­ results of these studies are summarized in tables I, 2 1 nisolone in a dose of about 40-60 mg·day· • Proximal and 3. MooRE et al. [8] investigated the effects of muscle weakness is a prominent clinical feature, pre­ cortisone on the diaphragm in rats (table 1). After venting patients from climbing stairs or elevating their daily intramuscular injection of 100 mg·kg- 1 cortisone arrns. Fluorinated steroids (such as triamcinolone and acetate for ten days the weight of the diaphragm de­ dexamethasone) seem to produce weakness and my­ creased by about 30%. The force generating capacity opathy more often than non-fluorinated corticosteroids of the diaphragm decreased in proportion to the reduc­ such as hydrocortisone and prednisone [1-3]. tion in weight, but was not altered when expressed per Serum levels of muscle e11zymes (creatine kinase unit cross-sectional area (table 2). During the force­ (CK), serum glutamic oxalo-acetic transaminase frequency curve fatigue (i.e. a reduction in maximal (SGOT) and aldolase) are usually normal [2, 3, 21]. fused tetanic tension) occurred in the control groups, Lactate dehydrogenase (LDH), however, was reported but not in the steroid-treated group. This may be ex­ to be elevated in one study of patients with systemic plained by a selective atrophy of the type lib fibres, lupus erythematosus [22], and in another paper on pa­ leaving muscle mainly composed of fatigue-resistant tients with COPD or asthma [15]. Creatine excretion type I and Ila fibres. in the urine is massively increased, from several days The effects of treatment over two weeks with corti­ before the clinical appearence of myopathy [3]. My­ sone acetate (10 mg·kg· 1 q·d.) on the diaphragm and oglobinuria or rhabdomyoJysis are absent. In biopsies the m. extensor digitorum longus (EDL), (a limb of the diseased muscles, the main finding is an atrophy muscle mainly composed of fast-twitch Ua and lib fi­ of type Jib fast-twitch glycolytic (FG) fibres [3-7]. bres) of rabbits were studied by FERGUSON et al. (11].

Table 1. Steroid-induced myopathy in animal studies Animal Steroid Body Diaphragm Soleus Gastro- EDL Reference n dose, duration weight weight weight cnemius weight weight

Rats cortisone acetate i.m. -14% -30% -36% -28% MOORE et al. (8] 11 100 mg·kg·' q.d. 10 days Hamsters triamcinolone i.m. -27% = -45% WILCOX et al. [9] 4 3 mg·kg·' q.d. 3 weeks Rats triamcinolone i.m. -30% -30% = -27% VURES et al. [10] 80 1.2 mg·kg·• q.d. 8 days Rats dexamethasone i.p. -18% -30% SASSON et al. [12] 10 1 mg·kg·• q.d. 2 weeks Rats dexamethasone i.p. -23% -32% = SASSON et a/. [12] 9 4 mg·kg·• q.d. 2 weeks Rats dexamethasone i.p. -25% -26% -28% SASSON et al. [12] 7 I mg·kg· 1 q.d. 7 weeks EDL: m. extensor digitorium longus; =: no change; - : not measured. STEROrD MYOPATHY AND RESPfRATORY DISEASE 999

Table 2. - Diaphragmatic contractile properties Animal Steroid Pt/CSA Po/CSA Pt/Po TPT 1/2 RT Force Fatigue Reference n dose, duration freq. curve Rats cortisone acetate i.m. = = = MOORE et al. [8) 11 100 mg·kg-' q.d. 10 days Hamsters triamcinolone i.m. +20% +31% i at 10, J. Wn.cox et al. [9) 4 3 mg·kg·• q.d. 3 weeks 20, 30Hz Rats triamcinolone i.m. -62% J. J. at 50 VrrREs et al. [10] 80 1.2 mg·kg·• q.d. 8 days and 100Hz Rats dexamethasone i.p = = = = = SASSON et al. [12) 10 1 mg·kg·• q.d. 2 weeks Rats dexamethasone i.p. -22% = J. at all = SASSON et al. (12) 9 4 mg·kg·' q.d. 2 weeks freq. Rats dexamethasone i.p. -31% -1 2% = -24% J. at all = SASSON et al. [12) 7 1 mg·kg·• q.d. 7 weeks freq. Pt: twitch tension; CSA: cross-sectional area; Po: tetanic tension; TPT: time-to-peak tension; 1/2 RT: half-relaxation time. =: no change; -: not measured.

Table 3. Histological, histochemical and biochemical changes in the diaphragm Animal Steroid Gross Histochemistry Biochemistry Reference ---n dose, duration pathology Rabbits cortisone acetate i.m. Vacuolization Glycogen i FERGUSON et al. [11] 9 10 mg·kg·• q.d. 2 weeks Fragmentation Myonecrosis Lactate i Rabbits cortisone acetate i.m. Vacuolization Fibre types = Glycogen i FERGUSON et al. [29] 13 10 mg·kg·• q.d. 3 weeks Myonecrosis Fibre CSA J. of all fibres Lactate i Hamsters triamcinolone i.m. More angulated Fibre types = Aggregate areas WILCOX et al. [9] 4 3 mg·kg·' q.d. 3 weeks muscle fibres of SDH staining in type I and II No myonecrosis lib fibre fibres size J. CSA: cross-sectional area; SDH: succinate dehydrogenase. =: no change; -: not measured.

Weight loss did not occur in these animals. Histo­ diaphragm per unit cross-sectional area did not change. logical examination of the diaphragm showed exten­ The force-frequency curve shifted to the left; the sive vacuolization, fragmentation of contractile material fatigability of the diaphragm was diminished. These and loss of fibre cross-sectional area (table 3). findings are expected to result from the relative in­ Glycogen and lactate levels were significantly elevated crease of type I and lla fibres, which are less fatigable in the diaphragm, whereas in the EDL only lactate was than the type lib fibres. The overall effect is expected increased. No significant pathological changes oc­ to be detrimental because of the loss of muscle mass. curred in the EDL. Maximal transdiaphragmatic Contrasting findings in rabbits, however, were ob­ pressure (Pdimax) was not altered by the treatment. tained in a later study from FERGUSON et al. [29]. In Respiratory muscle endurance, measured by inspiratory this study 28 rabbits were treated, during three weeks, threshold loading, was significantly decreased. These with cortisone acetate (10 mg·kg·• q.d. i.m.). In the results indicate that even with a moderate dose of diaphragm a reduction in size of all fibre types was cortisone acetate histological and biochemical changes shown, including type I fibres. Atrophy of type lib occur, resulting in a decrease in diaphragmatic endur­ fibres, but not of type I or IIa, was present in inter­ ance but not in strength. costal, sternocleidomastoid and EDL muscles. This Atrophy of type lib fibres of the diaphragm, with­ type I atrophy in the diaphragm may clearly affect the out changes in type I or Ila fibres, was found in endurance capacity of this muscle. The discrepancy hamsters treated with triamcinolone (3 mg·kg·• q.d.) between these fmdings and the results of WJLCOX et al. during two weeks [9]. Triamcinolone induced [9] may, in part, be related to species differences in profound loss of body weight. Maximal force of the fibre composition of the diaphragm and the response 1000 P.N.R. DEKHUUZEN, M. DECRAMER

to corticosteroids. Moreover, these differences may steroids, but did not provide further details on this further be explained by the use of a non-fluorinated statement. steroid, cortisone acetate [29], in contrast to triam­ PICADO et al. [33] studied the effects of the use of cinolone [9], a fluorinated steroid. The authors also steroids on the strength of the respiratory muscles and raise the possibility of a different corticosteroid the m. deltoideus in patients with asthma. Steroid­ receptor [30] and/or another type I fibre [31] in the dependent patients (n==34), who took an average dose diaphragm compared to peripheral and other respira­ of 12 mg·day· 1 during the last 8 yrs were compared tory muscles. to a group of non-steroid dependent asthmatic patients In another study [10], 80 rats were treated with a with the same age and sex distribution. P1max, maxi­ single injection of triamcinolone acetate 12 mg·kg·•, mal expiratory mouth pressure (PF.max) and the representing a daily dose of 1.2 mg·kg·•. After 8 days, strength of the m. deltoideus were not significantly total body weight and mass of the diaphragm and EDL different between the two groups. However, steroid decreased in proportion (about 30%). Transdiaphrag­ myopathy may not necessarily develop with these rela­ matic pressure during bilateral phrenic nerve stimula­ tively low doses of corticosteroids. Moreover, the tion at different frequencies and the force-frequency effects of repeated bursts of steroids were not appre­ curve in vitro showed no differences in the low fre­ ciated in this study. quency range, but a decrease at higher frequencies (50 JANSSENS and DECRAMER [13] described two patients and 100 Hz) compared to a control group. Significant, with collagen vascular disorders who showed a pro­ but smaller, changes were also noted in the EDL. gressive decrease in Punax and PEmax during treat­ Diaphragmatic peak twitch tension was not changed, ment with steroids. Gradual steroid tapering resulted but peak tetanic force was significantly decreased in in clinical improvement and marked increase in maxi­ the steroid-treated group. In this model, it is likely that mal mouth pressures, whilst creatinuria decreased. atrophy (reflected by the decreased weights of the In a study of 21 patients with COPD or asthma, muscles) as well as myopathy (indicated by the gen­ significant correlations were found between res­ eration of less force per unit cross-sectional area) were piratory and peripheral muscle strength and average induced. daily dose of steroids in the last six months [14]. Several treatment regimens in rats were compared in Eight of the 21 patients suffered from generalized the study of SASSON et al. [12]: dexamethasone in low muscle weakness. The average daily dose of methyl­ dose (1 mg·kg-1 q.d.) and high dose (4 mg·kg·• q.d.) prednisolone during the last six months exceeded 4 mg during two weeks, and prolonged treatment during in seven out of the eight patients, in contrast to only seven weeks with low dose dexamethasone (I mg·kg- 1 three of the 13 patients with normal muscle strength. q.d.). Dose-related weight loss was found in all ani­ W ANG et al. l34] compared the effects of 20 mg mals. Diaphragm weight loss was noted in the high prednisolone orally for two weeks in eight normal sub­ dose and the prolonged low dose groups. In these two jects in a placebo-controlled study. They found no treatment groups, maximal tetanic tension decreased ,significant effects on Ptmax, PEmax, Pdimax or significantly, and the force-frequency relationship was inspiratory muscle endurance. It is not excluded, how­ shifted to the right. The recovery from fatigue was ever, that the effects of steroids may be more pro­ not influenced by dexamethasone. nounced in the presence of other factors that affect From these animal studies, it is apparent that high diaphragmatic function, as in COPD patients. In ad­ doses of fluorinated [9, lO, 12] and non-fluorinated [8, dition, longer duration of treatment and higher doses 11] steroids, administered during short periods, may may be required to produce effects. severely affect diaphragmatic structure and function. In a recent report, two patients with asthma and one From the study of FERGUSON et al. [11], it can be con­ with COPD, who developed myopathy of respiratory cluded that changes may even occur with relatively and peripheral muscles during treatmen with methyl­ low doses of cortisone acetate. The effects of long­ prednisolone, were described [15] (figs. 1 and 2). term treatment with low doses of steroids remain to P1max and PEmax were reduced to mean 38% and be investigated, nor has the effect of intermittent 48% predicted, respectively, whilst quadriceps force therapy consisting of repeated bursts of steroid admin­ was reduced to 31% predicted. Tapering of the dose istration been studied. The latter two questions may was fo llowed by an increase to 74% and 92% of be of paramount importance to the treatment of COPD P1max and PEmax, respectively, after three months. and asthma patients. Quadriceps force increased to 62% after six months. These observations underline the potential hazards of treatment with corticosteroids, and the prolonged Steroid-induced changes in human duration of recovery after discontinuation of steroid respiratory muscles treatment. In an early report from BowYER et al. [32], respira­ tory and peripheral muscle strength were studied Pathogenesis and aetiology of steroid-induced in steroid-dependent asthmatic patients. Maximal atrophy and myopathy inspiratory mouth pressure (P1max) correlated with hip flexor strength. The authors also reported a good Pathological examination of muscles of patients correlation between P1max and the daily dose of treated acutely with high doses of systemic steroids STEROID MYOPATHY AND RESPIRATORY DISEASE 1001

reveals signs of massive necrosis and rhabdomyolysis The aetiology of steroid-induced changes is not of all fibre types [19]. There is a high concentration entirely clear. Glucocorticoids inhibit protein synthe­ of glycogen granules in the intermyofibrillar spaces sis and may accelerate myofibrillar and soluble protein [ 17]. Whether factors other than dose and type of degradation in skeletal muscle. These effects are more steroids administered play a role in the development pronounced in type II than in type I fibres. In addi­ of these changes is unclear. Disuse atrophy has been tion, carbohydrate metabolism is altered in steroid shown to be associated with an increase of cytoplas­ myopathy. Reduced muscle glycogen phophorylase mic steroid receptors [35]. It has been postulated that activity [5] and increased glycogen synthetase activ­ these steroid-induced changes may develop earlier in ity [37] lead to an increased intramuscular concentra­ patients during mechanical ventilation, especially when tion of glycogen. This impaired glycolytic activity they are paralysed for some days [20]. may, in part, be compensated by increasing oxidative In chronic steroid myopathy a distinctly different metabolism [6]. It might be speculated that the differ­ pattern of pathological changes is found. In this ences in response to steroids are, in part, explained by type, selective type lib fibre atrophy is found [25]. different contents of oxidative enzymes in type I and Fibre type distribution is not altered. Electron micro­ Ila fibres compared to type lib fibres. scopic examination shows mitochondrial aggregation, swelling and vacuolization, together with myofibrillar degeneration. Muscle spindle atrophy is only found Diagnosis of chronic steroid myopathy in type II fibres [36]. There is no clear correlation between the dosage or 100 duration of treatment and the development of myopa­ thy. Serum levels of muscle enzymes such as CK, • D SGOT and aldolase, are usually normal. LDH may 80 D 0 • sometimes be slightly elevated [15, 22]. The creatine "0 excretion in the urine is strongly elevated, starting ~ several days before the clinical appearence of myopa­ 0. 60 • ~0 thy [3]. Also, the course of the urine creatine levels • 0 X CIJ may be helpful, in combination with the clinical recov­ E ery after discontinuation of the treatment with steroids. a: 40 D "" "" • Pulmonary function tests are expected to be similar • to those observed in patients with respiratory muscle 20 weakness [38, 39]. A slightly restrictive pattern is found, due to reduced muscle force [13] . The diffu­ 0 sion capacity for carbon dioxide may be reduced 0 2 3 because of microatelectases [38]. Lung compliance is reduced with low recoil pressure at total lung capac­ Time months ity (TLC) [38]. This is in contrast with the pattern Fig. I. - P1max (% predicted) vs time (months) in three patients observed in interstitial lung disease in which elastic with COPD (0) or asthma (.&. .•) during reduction of steroid dose. P1max: maximal inspiratory mouth pressures; COPD: chronic recoil pressure at TLC is increased [40]. Measure­ obstructive pulmonary disease. (from [15], with permission). ments of P1max, PEmax and Pdimax disclose reduced values [14, 15]. Peripheral muscle strength (e.g. quad­ riceps force) is similarly reduced [15]. 100 . Biopsy of peripheral muscle shows selective type lib .. atrophy. Muscle glycogen content is increased . . D - Electromyographic findings are nonspecific. The "0 80 .. ~ .. -- motor unit potentials are of low amplitude and short 0. -- lilt -- duration [3, 21, 41]. ~0 ./ -- - Q) 60 . D · -- D ~ .' -- .E . en li Therapy of steroid-induced myopathy 0. p -' Q) 40 : (.) - .. g. -··'o ~ ' _ ...... The treatment of steroid myopathy consists mainly CIJ ' -- . ::I - ~ - - of reduction of the steroid dose, combined with con­ 0 20 ~ - version to a non-fluorinated steroid [1-3, 35, 42]. Androgens partially antagonize glucocorticoid-induced 0 muscle atrophy [21, 43, 44], in the diaphragm [45]. 0 2 3 4 5 6 The role of these anabolic steroids in patients with COPD or asthma who are treated with glucocorticoids Time months has not yet been elucidated. Fig. 2. - Quadriceps force (% predicted) vs time (months) in three patients with COPD (0) or asthma (.&., •> during reduction Physical exercises, such as weight-lifting [46] and of steroid dose. Same patients as in figure I. COPD: chronic treadmill walking [47] partially prevent steroid-induced obstructive pulmonary disease. (From [ 15], with permission) atrophy and weakness. 1002 P.N.R. DEKHUJJZEN, M. DECRAMER

References Ohi A, Inoue T. - Correlation between steroid myo­ pathy and serum lactate dehydrogenase in systemic J. Williams RS. - Triamcinolone myopathy. Lancet, lupus erythematosus. Arch Intern Med, 1981; 141: 1176- 1959; 1: 698-701. 1179. 2. Golding DN, Murray SM, Pearch GW, Thompson M. 23. Clark AF, Vignos PJ. - Experimental corticoster­ - Corticosteroid myopathy. Ann Phys Med, 1961; 5: oid myopathy: effect on myofibrillar ATPase activity 171 - 176. and protein degeneration. Muscle Nerve, 1979; 2: 3. Askari A, Yignos PJ, Moskowitz RW. - Steroid my­ 265- 273. opathy in connective tissue disease. Am J Med, 1976; 6 I: 24. Ruff RL, Martyn 0 , Gordon AM. - Glucocorticoid­ 485-492. induced atrophy is not due to impaired excitability in rat 4. MacLean K, Schurr PH. - Reversible amyotrophy muscle. Am J Plzysiol, 1982; 243: E512-E52l. complicating treatment with fluorocortisone. Lancet, 1959; 25. Ruff, R.L. - Endocrine myopathies. In: Engel AG, 1: 701-703. Banker BQ, eds. Myology. McGraw-Hill Book Co., 1986; 5. Smith B. - Histological and histochemical changes 1871- 1906. in the muscles of rabbits given the corticosteroid triamci­ 26. Goldberg AL, Goodman HM. - Relationship between nolone. Neurology. 1964; 14: 857- 863. cortisone and muscle work in determining muscle size. J 6. Yignos PJ, Greene R. - Oxidative respiration of skel­ Physio/, 1969; 200: 667-675. etal muscle in experimental corticosteroid myopathy. J Lab 27. Gardiner PF, Botterman BR, Eldred E, Simpson DR, Clin Med, 1973; 81: 365-378. Edgerton YR. - Metabolic and contractile changes in fast 7. Gardiner PF, Edgerton YR. - Contractile responses and slow muscle of the cat after glucocorticoid-induced of rat fast-twitch and slow-twitch muscles to glucocorticoid atrophy. Exp New·ol, 1978; 62: 241-255. treatment. Muscle Nerve, 1979; 2: 274-281. 28. Roy RR, Gardiner PF, Simpson DR, Edgerton YR. - 8. Moore BJ, Miller MJ, Feldman HA, Reid MB. - Dia­ Glucocorticoid-induced atrophy in different fibre types of phragm atrophy and weakness in cortisone-treated rats. J selected rat jaw and hind-limb muscles. Archs Oral Bioi, Appl Physiol, 1989; 67: 2420- 2426. 1983; 28: 639-643. 9. Wilcox PG, Hards JM, Bockhold K, Bressler B, Pardy 29. Ferguson GT, lrvin CG, Cherniack RM. - Effects of RL. - Pathologic changes and contractile properties of the corticosteroids on respiratory muscle histopathology. Am Rev diaphragm in corticosteroid myopathy in hamsters: compari­ Respir Dis, 1990; 142: 1047- 1052. son to peripheral muscle. Am J Respir Cell Mol Bioi, 1989; 30. Carlstedt-Duke J, Gustafsson JA. - Structure and 1: 191-199. function of the glucocorticoid receptor. J Steroid Biochem, I 0. Viires N , Pavlovic D, Pariente R, Aubier M. - Ef­ 1987; 27: 99-104. fects of steroids on diaphragmatic function in rats. Am Rev 31. Reid MB, Ericson GC, Feldman HA, Johnson RL. - Respir Dis, 1990; 124: 34-38. Fibre types and fibre diameters in canine respiratory mus­ ll. Ferguson GT, Jrvin CG, Chemiack RM. - Effects of cles. ' App/ Physiol, 1987; 62: 1705-17 I 2. corticosteroids on diaphragm function and biochemistry in 32. Bowyer SL, La Mothe MP, Hollister JR. - Steroid the rabbit. Am Rev Respir Dis, 1990; 141: 156-163. myopathy: incidence and detection in a population 12. Sasson L, Tarasiuk A, Heimer D, Bark H. - Effect with asthma. J Allergy Clin lmmunol, I 985; 76: 234- of dexamethasone on diaphragmatic and soleus muscle 242. mor-phology and fatigability. Respir Physiol, 1991; 85: 15- 33. Picado C, Fiz AJ, Montserrat JM, Grau JM, Femandez­ 28. Sola J, Luengo MT, Casademont J, Agusti-Yidal A. - 13. Janssens S, Decramer M. - Corticosteroid-induced Respiratory and skeletal muscle function in steroid­ myopathy and the respiratory muscles. Report of two cases. dependent bronchial asthma. Am Rev Respir Dis, 1990; 141: Chest, 1989; 95: 1160-1162. 14-20. 14. Rogiers Ph, Lacquet LM, Decramer M. - Steroid­ 34. Wang Y, Zintel T, Yasques A, Gallagher CG. - Cor­ induced myopathy in patients with COPD and asthma. ticosteroid therapy and respiratory muscle function in (Abstract). Eur Respir J, 1991 ; 4: 346. humans. Am Rev Respir Dis, 1991; 144: 108- 112. 15. Decramer M, Stas KJ. - Corticosteroid-induced my­ 35. DuBois DC, Almon RR. - Disuse atrophy of skeletal opathy involving respiratory muscles in patients with COPD muscle is associated with an increase in number of or asthma. Am Rev Respir Dis, 1992, (In Press). glucocorticoid receptors. Endocrinology, 1980; 107: 1649- 16. MacFarlane lA, Rosenthal FD. - Severe myopathy 165 I. after status asthmaticus. Lancet, 1977; ii: 615. 36. Stern LZ, Hannapel LK. - The muscle spindle in 17. van Marle W, Woods KL. - Acute hydrocortisone cortisone-induced muscular atrophy. Exp Neurol. 1973; 40: myopathy. Br Med J, 1980; 281: 271-272. 484-490. 18. Knox AJ, Mascie-Taylor 8, Muers MF. - Acute hy­ 37. Shoji S, Takagi A, Sugita H, Toyokura Y. - Muscle drocortisone myopathy in acute severe asthma. Thorax, glycogen metabolism in steroid-induced myopathy of rab­ 1986; 41: 411-412. bits. Exp Neurol, 1974; 45: l-7. 19. Williams TJ, O'Hehir RE, Czuruy D, Home M, Bowes 38. De Troyer A, Botenstein S, Cordier R. - Analysis G. - Acute myopathy in severe acute asthma treated with of lung volume restriction in patients with respiratory mus­ intravenously administered corticosteroids. Am Rev Respir cle weakness. Thorax, 1980; 35: 603-610. Dis, 1988; 137: 460-463. 39. Braun NMT, Arora NS, Rochestcr OF. - Respiratory 20. Shee CD. - Risk factors for hydrocortisone myo­ muscle and pulmonary function in polymyositis and other pathy in acute severe asthma. Respir Med, 1990; 84: proximal myopathies. Thorax, 1983; 38: 616- 623. 229- 233. 40. Yemault JC, De Jonghe M, De Coster A, Englert M. 21. Afifi AK, Bergman RA, Harvcy JC. - Steroid my­ - Pulmonary mechanics in diffuse fibrosing alveolitis. Bull opathy. Clinical, histologic and cytologic observations. John Eur Physiopathol Respir, 1975; 11: 231 - 234. Hopkins Med J, 1968; 123: 158-174. 41. Yates DAH. - Steroid myopathy. Rheumatol Phys 22. Kanayama Y, Shiota K, Horiguchi T, Kato N, Med, 1971; 11: 28-33. STEROID MYOPATHY AND RESPIRATORY DISEASE 1003

42. Duvenci J, Chodosh S, Segal MS. - Dexamethasone 45. Reid MB, Wang N, Haack KE, Miller MJ. -Anabolic therapy in bronchial asthma. Ann Allergy, 1959; 17: 695- steroids protect skeletal muscles against cortisone-induced 700. atrophy. (Abstract). Faseb J, 1990; 4: 1068. 43. Sakai Y, Kobayashi K, Twata N. - Effects of 46. Gardiner PF, Hibl B, Simpson DR, Roy R, Edgerton anabolic steroids and vitamin B complex upon myopathy YR. - Effects of a mild weight-lifting program on the induced by corticosteroids. Eur J Physiol, 1978; 52: 353- progress of glucocorticoid-induced atrophy in rat hindlimb 359. muscles. Pflugers Arch, 1980; 385: 147-153. 44. Santidrian S, Young YR. - Effect of androgens on 47. Hickson RC, Davis JR. - Partial prevention of glu­ the rate of muscle protein breakdown in rats treated with cocorticoid-induced muscle atrophy by endurance training. glucocorticoids. Reproduction, 1980; 4: 331- 337. Am J Physiol, 1981; 241: 226-232.