Clinical and experimental skeletal muscle alcoholic myopathy

Abstract

Musculoskeletal symptoms are frequent in chronic alcohol abusers, but only relatively recently has a search been made for the pathological basis of these complaints. A prospective study of 150 unselected patients admitted with various forms of alcohol abuse, showed that on quadriceps muscle biopsy two-thirds of the patients had significant and specific atrophy of the type IIB (anaerobic, fast-twitch) muscle fibres (Martin & Peters, 198Sa,h). Half of the patients do show significant proximal muscle weakness which may be quite disabling. The histochemical lesion is, however, reversible with abstinence over 612 months (Slavin et al., 1 983), but the reason for the individual patient susceptibility to the myopathy of chronic ethanol abuse is uncertain. The lesion is not closely correlated with degree or duration of alcohol abuse (Martin et al., 1985a,h), nutritional status (Duane & Peters, 1988a), glucocorticoid excess (Duane & Peters, 1987), peripheral neuropathy (Mills et a/.. 1 986) or the presence of other complications, e.g. cirrhosis, cardiomyopathy (Martin et a/., 1985). Recent studies of the antioxidant status of the patients, i.e. plasma a-tocopherol and selenium levels, do show a selective reduction in patients with myopathy compared with controls or non-myopathic alcoholics (Ward et al., 1 9 8 7 ~ ) . It is unlikely that these reduced levels are due to dietary deficiency or malabsorption of a-tocopherol and selenium, but they suggest that enhanced free radical activity may be involved in the pathogenesis of the lesion. It would be clearly useful to be able to diagnose and monitor alcoholic myopathy without repeated muscle biopsies. Consideration of the biochemical differences between type 1 and type I 1 fibres indicated that type I1 fibres are particularly rich in histidyl dipeptides including carnosine (Tamaki et ul., 1977). Although the function of these peptides is unknown, preliminary tissue analyses revealed reduced levels in myopathic biopsies compared with controls. Following this observation, an assay for serum carnosinase (EC 3.4.1 3.3) was established. Reduced activity was found in patients with myopathy, with a return to control values on prolonged abstinence (Duane et al., 1986). There was a good correlation between serum carnosinase activity and degree of fibre atrophy and muscle mass as measured by the creatinine height index (Duane & Peters, 10886). The reason for the reduced serum carnosinase in patients with alcoholic myopathy is not understood. It is, however, clinically useful in assessing these patients, both in diagnosis and management. Further studies on the pathogenesis of chronic skeletal muscle myopathy have been inhibited by the lack of a suitable animal model. Previous reports have demonstrated mitochondria1 changes by electron microscopy in muscle tissue from adult alcohol-fed rats (Shaw et a/., 1982). However, although this lesion may have features in common with acute myopathy affecting type I fibres, it clearly does not mirror the chronic type 11 fibre atrophy seen in man. Recently, chronic ethanol-feeding experiments, particularly in actively growing rats, caused selective damage of the type I1 fibre-rich muscles (Ward et a/., 19876; Preedy et af . , 1 9 8 8 ~ ) . In the younger rats a strikingly selective reduction of type I1 rich fibre muscle weight has been achieved (Table 1). This is particularly marked in the quadratus lumborum which is approximately 30% smaller after 6 weeks feeding of the ethanol diet compared with the pair-fed controls. This model will enable a variety of questions concerning the particular susceptibility of type I1 fibres to ethanol toxicity Table 1. Body and m r t . s c k ~ weight and niriscYe K N A cont(wi in cmrrol and dcohol-fed ruts