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With the advent of functional electrical stimulation (FES) there is the possibility of paraplegic patients regaining some degree of locomotor activity. It is of interest to document the changes in composition histochemistry and size of muscle fibres in such patients both before and after such therapy. We have examined biopsy specimens from quadriceps muscles obtained from 7 male patients, age range 24-47 years, who had been paraplegic for times ranging from 11 months to 9 years and we report the histochemical appearance of the muscle the fibre type composition and the mean fibre areas. In 5 of the 7 subjects there was a marked or complete predominance of fibres which stained as type 2 with the ATPase reaction at pH 9.4. At acid pH these fibres were seen to be predominantly 2B (fast fatigable). The 2 subjects who had been paralysed for the shortest periods had proportions of type 1 fibres which were relatively well preserved. The mean fibre areas of type 2 fibres were below the normal range (2500-7500 microns 2) in every case as were the type 1 fibres in the 4 patients in which these were still present. There was no relationship between the length of time the patient had been paralysed and the mean fibre areas which suggests that atrophy occurs fairly quickly following loss of voluntary control and precedes the loss of type 1 characteristics. Our findings provide an explanation for the rapid onset of fatigue in paraplegic patients taking part in FES programmes since muscles deficient in type 1 fibres will be unable to maintain force for any length of time.

The histology of needle biopsy specimens of skeletal muscle from the vastus lateralis was quantitatively assessed in a group of adults with growth hormone (GH) deficiency, most of whom had hypopituitarism treated with conventional pituitary hormone replacement. The mean age of the 21 patients (16 males and 5 females) was 39 +/- 2 (SEM). Comparisons were made with age- and sex-matched controls following six months double-blind, placebo-controlled treatment with recombinant human GH (rhGH) in the GH-deficient patients. Before treatment, needle muscle biopsies from patients with GH deficiency showed mean type I and II fibre areas of 5,153 +/- 273 and 4,828 +/- 312 microns 2 respectively, which did not differ from the controls (4,482 +/- 306 and 4,699 +/- 310 microns 2). Percentages of type I fibres were similar in the two groups (47.2 +/- 2.5% in GH deficiency and 45.3 +/- 2.2% in controls). No difference in the variability of type I or II fibre areas was demonstrated between the groups. Correlations between the relative contribution to total fibre area by type I fibres (mean fibre area x percent) and maximal oxygen uptake (p = 0.006), and between type II fibres and quadriceps force (p = 0.035) were noted in GH-deficient adults before treatment. Following rhGH treatment, no change was noted in mean fibre areas, variability of fibre areas, or percentage of either fibre type.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: The aim of this study was to determine whether there are any changes in skeletal muscle strength and size and body composition following growth hormone (GH) withdrawal in GH deficient young adults., Design: A longitudinal, 1-year, open, uncontrolled study of the changes in skeletal muscle and body composition following GH withdrawal was performed. Endocrine status was reassessed at the end of the study period during an insulin tolerance test. Some measurements were repeated after 2 years of treatment., Patients: Twelve (11 male, one female; age range 14-21) patients who had been diagnosed during childhood as growth hormone deficient took part in the study. Four of the 12 patients were found to have a normal GH response on retesting at the end of the study and their results were analysed as a separate group., Measurements: Quadriceps and forearm flexor maximum voluntary isometric strength, body fat content and serum IGF-1 were measured at 3-monthly intervals over 1 year. Every 6 months muscle size was measured from computerized tomography scans and fibre area from quadriceps needle biopsy samples., Results: For the growth hormone deficient group the 12 month quadriceps strength, size and fibre areas were 94.0% +/- 8.5 (mean +/- SD), 94.5% +/- 6.3 and 85.6% +/- 17.7 respectively of control (baseline) values. Forearm flexor strength and size were 101.4% +/- 7.9 and 92.0% +/- 9.2 of control. Body fat percentage had increased from 19.5% +/- 8.6 to 24.1% +/- 9.5. No change was seen in the non-growth hormone deficient group., Conclusions: Although the changes measured were relatively small they suggest a role for GH in the maintenance of muscle integrity and body composition in the young adult with growth hormone deficiency.

Proportions of slow (type 1) muscle fibres of the vastus lateralis and percentage body fat were measured in 11 healthy sedentary men. The proportion of slow muscle fibres was inversely related to fatness; at least 40% of the variability in fatness may be related to variation in muscle fibre type. Metabolic evidence in 50 men, provided by the respiratory exchange ratio (RER) during cycle ergometry, indicated that fatter men (or, in the subset of 11 men, those with a low proportion of slow muscle fibres) combusted less fat during work at 100 W than did lean men (or those with a high proportion of slow fibres). The effects of fitness and of body size were excluded in the analysis. The evidence supports the hypothesis that muscle fibre type is an aetiological factor for obesity.

Quadriceps strength and size was measured in a small group of subjects (n = 7) 1 to 5 years after full mobilisation following some form of unilateral lower limb trauma. The mean maximum voluntary isometric force (MVC) was significantly lower for the injured (I) compared to the uninjured (UI) leg (369 N +/- 139 vs. 535 N +/- 131, p less than 0.01). Electrical stimulation superimposed on the voluntary contractions demonstrated that all subjects were able to maximally activate the quadriceps of both legs. Mean quadriceps cross-sectional area (CSA) was significantly lower in the I (64 cm2 +/- 12.8) compared to the UI leg (80 +/- 12.8, p less than 0.01). One subject with marked unilateral weakness and wasting took part in a 3-month strength training study for the injured leg. After training the I/UI ratio had been restored to nearly 100% (94% MVC; 88% CSA). These results would suggest that longer and more intensive physiotherapy is required in the immediate post-injury period to restore muscle strength and size to severely atrophied muscle.

Over 1,000 needle biopsies have been carried out at University College Hospital in London. Needle biopsy has been used by us for histochemical and electron microscopic examination of muscle during the diagnosis and treatment of neuropathic and myopathic disorders, for the diagnosis of mitochondrial myopathies, to study the course of recovery in polymyositis, and for investigations into muscle changes in systemic lupus erythematosus (SLE) and other autoimmune conditions. We have developed a microprocessor system for the measurement of muscle fiber areas, and needle biopsy specimens provide suitable material for such measurements. We have also used needle biopsy specimens for studies of protein turnover using stable isotopes and for trace metal and electrolyte analyses. Needle biopsy is safe and rapid. As the patient usually experiences only minimal discomfort and there is no permanent scar, repeat biopsies are well tolerated allowing follow-up studies after treatment.

We have examined the anatomy and fibre type composition of the human adductor pollicis in muscles taken post mortem. Histochemical staining of muscle fibres showed that type I fibres predominated in all cases with a mean occurrence of 80%. This composition is similar to that of the soleus muscle and unlike that of the quadriceps which has approximately equal proportions of the two fibre types. Comparing the contractile characteristics, however, the adductor pollicis has similar properties to the quadriceps and both are quite distinct from those of the slowly contracting soleus muscle. The lack of correlation between fibre composition, as revealed by histochemical staining, and contractile properties in these muscles must mean that fibres of the same type from different muscles do not necessarily have the same contractile speed. The results also suggest that the type I fibres of the human adductor pollicis are faster than those of both the soleus and quadriceps muscles.

We have examined muscle strength, mitochondrial enzyme activity, histochemistry and fibre size in the quadriceps muscle of 9 patients with severe chronic heart failure. A needle biopsy of the quadriceps muscle was taken with patients at rest. Maximum oxygen uptake was measured during treadmill exercise. Mean maximal oxygen consumption was 11.7 ml.kg-1.min-1. Isometric maximum voluntary contraction was reduced to 55% of the predicted value for weight. Eight biopsies were abnormal. Findings included increased acid phosphatase, increased interstitial cellularity, excess intracellular lipid accumulation, atrophy of both type I and II fibres and variation in size with hypertrophy and atrophy of fibers. Muscle fibre capillary density and the activity of mitochondrial enzymes were normal. Changes in skeletal muscle strength may play a role in the limitation of exercise capacity seen in patients with congestive heart failure.

The type and distribution of mononuclear cell infiltrates in muscle biopsies taken from 9 subjects at differing times after exercise in which the muscle is stretched (eccentric exercise) has been characterised. The appearances are compared to those seen in muscle from patients with inflammatory muscle disease. After exercise infiltrating cells were seen in perivascular, perimysial and endomysial regions, the extent being greater in the later biopsies (9-14 days). The predominant cell type was the macrophage (46-100% of all infiltrating cells), the remainder were T lymphocytes with a predominance of the CD4 positive helper/inducer subset. Approximately one third of the T cells expressed DA2 (class 2) antigen indicating that they were activated. Very few B lymphocytes and no Leu7 positive cells were seen. There was evidence of class 1 expression on some of the damaged muscle fibres. The appearance of the experimentally damaged muscle in normal subjects was very similar to untreated polymyositis suggesting that a proportion of the infiltrating cells seen in this disease may be present as part of a natural response to damage rather than being its cause.

Our purpose was to determine the amount of injury to extensor digitorum longus (EDL) and anterior tibial (ATB) muscles of mice from 1 h to 30 days following passive shortening and lengthening, shortening contractions and lengthening contractions. The shortening-lengthening cycle was of 600 ms duration and was repeated every 5 s for 30 min. Contractions were produced during either the shortening or lengthening phase with stimulation at 100 Hz for 300 ms. The amount of injury was evaluated by the decrease in the number of fibres in a cross-section of the muscle and in the maximum isometric tetanic force (Po). Passively shortened and lengthened and actively shortened EDL and ATB muscles showed no evidence of injury. At 3-5 days after lengthening contractions, EDL and ATB muscles showed an inflammatory response. At 3-5 days, the number of fibres in the cross-section of the injured EDL muscles was 65% of that of the contralateral control EDL muscle, whereas no change was observed in the number of fibres in the injured ATB muscles. By 3 days, the presence of myoblasts, myotubes and central nuclei indicated regeneration of fibres. One hour after shortening contractions, the Po of EDL and ATB muscles decreased to about 75% of the contralateral control value, but recovered completely by 3 days. In contrast, 1 h after lengthening contractions the Po of EDL and ATB muscles decreased to 52 and 40% respectively of the contralateral control value and then both recovered to about 65% within 3 h. For the ATB muscle, the Po showed a secondary decrease to 49% of the contralateral control value at 1 day and for the EDL muscle, to 47% at 3 days. Each muscle recovered gradually and by 30 days the number of fibres and the Po of the injured muscles were not significantly different from values for contralateral control muscles.

Calf and quadriceps muscle size and composition have been examined in 5 control subjects and 12 boys (aged 7-18 years) with Duchenne muscular dystrophy using computed tomography (CT) and quantitative histochemistry of needle biopsy samples of muscle. In assessing the size of leg muscles it was found that in control subjects the muscle cross-sectional area was related to the cross-sectional area of the femur. The calf muscles in the patients were enlarged both relative to the quadriceps and absolutely when related to the cross-sectional area of the femur used as an index of stature. The enlargement of the calf was the result of accumulations of fat and connective tissue in the presence of relatively normal (compared to femur size) amounts of muscle tissue. Although hypertrophied muscle fibres were a feature of the biopsy samples in the calf the extent of this was insufficient to contribute appreciably to the total muscle enlargement.

Skeletal muscle strength and size were measured for 1 year following discontinuation of human growth hormone (hGH) treatment in 11 patients with hypopituitarism. Quadriceps and forearm flexor maximum voluntary isometric strength and size were measured. At the end of the study, endocrine status was reassessed by an insulin tolerance test. Three of the 11 subjects were found to have normal hGH secretion and were not included in the analysis. At 12 months, quadriceps strength, size and fibre areas were 94.0 +/- 8.5%, 94.5 +/- 6.3% and 85.6 +/- 17.7% (mean +/- SD), respectively, of baseline values. Forearm flexor strength and size were 101.4 +/- 7.9% and 92 +/- 9.2% of control values. Although these changes are relatively small, they suggest a role for growth hormone in the maintenance of muscle in the adult.

Seventeen volunteers performed unilateral strength-training of the quadriceps with high-resistance, low-repetition, dynamic exercise, thrice weekly for an average of 5 weeks. Both before and after the training period, bilateral measurements were made of isometric quadriceps strength, quadriceps cross-sectional area (by ultrasound scanning), and thigh circumference. There were no significant changes in the untrained thighs. The trained quadriceps increased their isometric strength by more than they changed their cross-sectional area (mean increments = 15% and 6% respectively). Quadriceps hypertrophy was underestimated by measurements of thigh circumference and could not be predicted from them. We conclude that studies of localized muscle growth require direct measurements of the size of the muscle(s) concerned. Nevertheless, these may still underestimate the improvements in strength produced by high-resistance training.

Muscle breakdown and repair were measured by metabolic balance techniques in a patient with polymyositis who was being treated with prednisolone and azathioprine. Changes in body muscle mass that had been estimated from nitrogen and phosphorus balances correlated with antropometric assessments of thigh muscle mass and quadriceps strength. Decline in muscle strength was associated with a net rate of muscle breakdown of 148 g/day. Recovery was associated with a net rate of muscle repair of up to 100 g/day. Early reduction in corticosteroid treatment appeared to enhance the rate of repair. Changes in the isometric contraction force of the quadriceps muscle (but not in clinical symptoms, plasma creatine kinase [CK] or erythrocyte sedimentation rate [ESR] were found to reliably indicate whether the muscle was in a state of breakdown or repair. Treatment of the individual patient may be quantitatively monitored by metabolic balance studies or, more simply, by measurement of muscle strength.

The effects of eccentric exercise have been examined in human calf and biceps muscles. Release of muscle creatine kinase and uptake of technetium pyrophosphate have been followed for up to 20 days after the exercise and the results are related to the morphological changes seen in needle biopsy samples. The response to exercise was variable, all subjects developing pain and tenderness in the exercised muscles after 1-2 days and this was followed, in most subjects, by a large increase in plasma creatine kinase 4-6 days after the exercise. This was paralleled by an increased uptake of technetium pyrophosphate into the exercised muscle. Biopsies of the affected muscles showed little or no change in the first 7 days after the exercise but later degenerating fibres were seen, as well as infiltration by mononuclear cells and eventually, by 20 days, signs of regeneration. Very extensive changes were seen in the calf muscle of one subject; changes in the biceps were qualitatively similar but not so severe. In the severely affected calf muscle type II fibres were preferentially damaged. Mononuclear cell infiltration both between and within degenerating fibres was maximal well after the time of peak plasma creatine kinase and it is likely that in eccentrically exercised muscle infiltrating mononuclear cells act to scavenge cellular debris rather than to cause damage to the muscle.

Needle biopsies from vastus lateralis in untreated hypothyroid patients with muscle weakness confirmed by quadriceps force measurements (n = 11) were repeated when the patients had taken L-thyroxine for a mean period of 9.2 months (range 5.3-13.3 months, n = 8) and had been continuously biochemically euthyroid for a mean period of 4.9 months (range 2-11 months). Biopsies were analysed biochemically for mitochondrial function. On light microscopy, histochemical examination, mean fibre areas and fibre percentages of type I and type II fibres were determined. Electronmicroscopy was also performed. Abnormalities on light microscopy occurred in eight patients of which type II fibre atrophy was the commonest and of the remainder two patients showed a myopathic electromyogram (EMG) and a raised plasma creatine kinase activity and one ultrastructural change on biopsy. After treatment resolution of pathological changes was often slow and half the patients had persistent abnormalities when rebiopsied. The type I mean fibre area was significantly increased in the eight hypothyroid females (p less than 0.05) and type II mean fibre areas tended to be low and in females this was significant (p less than 0.05). After treatment the type I mean fibre area was significantly reduced (p = 0.05). The type II mean fibre area also tended to fall but this was not significant (p greater than 0.05). No change in the fibre percentages occurred. A myopathic EMG, a raised plasma creatine kinase activity, ultrastructural changes and low mitochondrial enzyme activities on needle biopsy were other common findings and their significance is discussed.

By means of ultrasound scanning, bilateral measurements of the cross-sectional area of the quadriceps muscle groups were made in 14 young adults with unilateral thigh muscle wasting after knee injury. Needle biopsy specimens from the lateral mass of the muscle were used to estimate the myofibre cross-sectional area for both quadriceps of each subject. 2. The cross-sectional area of the quadriceps of each patient's injured limb was always smaller than that of the contralateral muscle. The wasting was largely localized to the quadriceps, with relative sparing of the other thigh muscles. 3. None of the biopsies showed any abnormality apart from the reduction in fibre size. In each case, the injured limb's reduced quadriceps cross-sectional area was associated with a reduced mean fibre area. 4. The ratio of the cross-sectional area of a muscle to its mean fibre area is a reduced mean fibre area. 4. The ratio of the cross-sectional area of a muscle to its mean fibre area is a function of the number of fibres it contains. The ratio varied considerably from patient to patient but there was close agreement between the values obtained for the two limbs of each patient. 5. The quadriceps wasting produced by knee injury was due to muscle fibre atrophy. There was no evidence for a change in the number of fibres in the muscle.

The time course of recovery in the myopathy of Cushing's syndrome was studied before and after removal of a pituitary adenoma at hypophysectomy in three patients and an adrenal adenoma in another. Serial measurements were performed of quadriceps force, total muscle mass/body weight, individual fibre size on needle biopsies of the lateral muscle mass of the thigh and skeletal muscle cross-sectional area (CSA) and force/unit CSA on computed (CT) scans of thighs and calves. All patients were weak, and recovery was slow but substantial except in one patient who had persistent Cushing's syndrome. An accompanying increase in overall and type II mean fibre area (MFA) occurred after surgery in the patients with a pituitary adenoma, as did an increase in skeletal muscle CSA and force/unit CSA in both patients having CT scans. The only patient with pronounced muscle wasting showed severe type II fibre atrophy with a reduced total muscle mass/body weight, but muscle morphology and total muscle mass were normal in the other patients. Only in this patient was a significant increase in total muscle mass/body weight noted after surgery. These findings suggest that the increase in muscle mass which may follow hypophysectomy in Cushing's syndrome is due to an increase in individual cell size.