Free and total carnitine and acylcarnitine content of plasma, urine, liver and muscle of alcoholics

1. Plasma and urine free and total carnitine and acylcarnitine levels were assayed in 12 control subjects and 20 chronic alcoholics with fatty liver. Although the alcoholics had a wider range of values than the controls, there was no significant difference between the two groups. 2. Hepatic free and total carnitine and long- and short-chain acylcarnitines were assayed by a radioenzymatic method in samples from seven control subjects and seven alcoholics. No significant differences in any of the indices were noted between the patient and control groups and it was concluded that carnitine deficiency did not contribute to alcoholic fatty liver in patients without cirrhosis. 3. Skeletal muscle free and total carnitine and long- and short-chain acylcarnitines were assayed in eight alcoholics and seven control subjects. The alcoholics had significantly higher total and free carnitine levels. It is suggested that this reflects a selective enrichment of the biopsy sample with type I carnitine-rich fibres due to the type II fibre atrophy found in approximately half the patients.     

Serum carnosinase activities in patients with alcoholic chronic skeletal muscle myopathy

1. Serum carnosinase activity was assayed in a group of alcoholic patients with and without histologically proven atrophy of type II skeletal muscle fibres, and in control subjects. No significant activity was detected in muscle biopsy samples or washed erythrocytes. 2. Serum carnosinase activity was significantly lower in chronic alcoholic patients compared with a group of age-matched controls. Alcoholics with abnormal muscle biopsies had significantly lower enzyme activities than either those patients with normal muscle biopsies or the controls. Serum enzyme activities in patients with normal muscle biopsies were not significantly different from controls. 3. Serum carnosinase activity was inversely correlated with the degree of muscle atrophy as measured by the type II fibre atrophy factor. There was a positive correlation between the enzyme activity and skeletal muscle mass as reflected by the creatinine-height index. Furthermore, the enzyme activity significantly increased, with resolution or improvement in the myopathy, in patients who abstained from alcohol. 4. Kinetic studies showed that the reduced carnosinase activity was due mainly to a decrease in the apparent Vmax. The apparent Km was significantly higher in the myopathic compared with non-myopathic alcoholics. Mixing serum from controls and patients with myopathy gave the expected values, indicating the absence of a serum enzyme inhibitory factor. Acute alcohol loading had no effect on the serum carnosinase activity. 5. The decrease in serum carnosinase activity in alcoholics was not related to the severity of their liver disease. Assays of serum carnosinase in chronic alcoholics, can thus be used as a marker of their associated myopathy.     

Vitamin D deficiency and muscle strength in male alcoholics

1. Chronic alcoholism may be complicated by proximal muscle weakness associated with a selective atrophy of type II skeletal muscle fibres. The histopathological findings are non-specific as identical changes are seen in proximal muscle weakness associated with various metabolic myopathies, including osteomalacia. 2. The maximum voluntary contraction (MVC) of the dominant quadriceps and plasma 25-hydroxycholecalciferol [25-(OH)D] were measured in male alcoholics and control subjects to determine whether vitamin D deficiency contributed to proximal muscle weakness. 3. In both groups MVC declined with age and was related to body build. The distribution of plasma 25-(OH)D was skewed in alcoholics, with the mean significantly lower than in control subjects. Seventeen per cent of patients (but none of the control subjects) had pronounced biochemical deficiency [plasma 25-(OH)D less than 10 nmol/l]. 4. Alcoholics were significantly weaker than control subjects, even after correcting for the effects of age, height and weight. The severity of associated liver disease (cirrhosis vs no cirrhosis) did not influence muscle strength. Variation in plasma 25-(OH)D and albumin made an insignificant contribution to the difference in MVC observed between patients and control subjects. 5. We conclude that proximal muscle strength is reduced in chronic alcoholism but that this is not due to associated vitamin D [25-(OH)D] deficiency or alcoholic cirrhosis.     

Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle.

Previous studies provided evidence that sepsis-induced muscle proteolysis in experimental animals is caused by increased ubiquitin-proteasome-dependent protein breakdown. It is not known if a similar mechanism accounts for muscle proteolysis in patients with sepsis. We determined mRNA levels for ubiquitin and the 20 S proteasome subunit HC3 by Northern blot analysis in muscle tissue from septic (n = 7) and non-septic (n = 11) patients. Plasma and muscle amino acid concentrations and concentrations in urine of 3-methylhistidine (3-MH), creatinine, and cortisol were measured at the time of surgery to assess the catabolic state of the patients. A three- to fourfold increase in mRNA levels for ubiquitin and HC3 was noted in muscle tissue from the septic patients concomitant with increased muscle levels of phenylalanine and 3-MH and reduced levels of glutamine. Total plasma amino acids were decreased by approximately 30% in the septic patients. The 3-MH/creatinine ratio in urine was almost doubled in septic patients. The cortisol levels in urine were higher in septic than in control patients but this difference did not reach statistical significance. The results suggest that sepsis is associated with increased mRNAs of the ubiquitin-proteasome pathway in human skeletal muscle.     

Effects of chronic ethanol abuse on structure and enzyme activities of skeletal muscle in man.

Biopsies from vastus lateralis muscle of male patients suffering from chronic ethanol abuse were studied with regard to histochemical reactions of ATPase and NADH-diaphorase; enzymatic activities of triosephosphate dehydrogenase (TPD), lactate dehydrogenase (LD), and cytochrome c oxidase (cytox); content of ATP, creatine phosphate, and glycogen; and volume fractions of fat, mitochondria, and fibrillar and extrafibrillar space. The results were compared with those from controls without known abuse of ethanol. The relative numbers of fibers were the same in two groups, but the size of the fast-twitch-glycolytic (white) fibers was diminished in the alcoholic group. The activities of TPD and LD were diminished in skeletal muscle of the alcoholics. This is most probably caused by the reduced amount of fast-twitch-glycolytic tissue, as there was a good correlation between this amount and the activity of the two enzymes. The activity of cytox was slightly lower in muscle of the alcoholics than in that of the controls. The volume fraction of mitochondria was lower in the alcoholic group than in the control group. Volume fractions of fat and fibrillar and extrafibrillar space were equal in the two groups. No significant differences were found in the amount of glycogen and ATP in the muscle of the two groups. However, the content of creatine phosphate is higher in the alcoholic group than in the control group.     

Increased turnover of muscle contractile proteins in Duchenne muscular dystrophy as assessed by 3-methylhistidine and creatinine excretion.

1. Myofibrillar protein degradation has been measured in patients with Duchenne muscular dystrophy, normal boys, adult males and Duchenne carriers by the rate of 3-methylhistidine excretion after transfer of subjects to a meat-free diet. 2. Although absolute rates of protein breakdown are lower in Duchenne patients, expression of the data to allow for differences in muscle mass gives fractional degradation rates 2--3 times higher than in age-matched controls. 3. Fractional rates of muscle protein synthesis are increased in the Duchenne patients to almost the same extent as protein breakdown. 4. Rates of muscle protein breakdown in obligate and presumed carriers of the Duchenne gene are not different from controls.     

Skeletal muscle and whole-body protein turnover in cirrhosis

1. We investigated arteriovenous exchanges of tyrosine and 3-methylhistidine across leg tissue in the postabsorptive state as specific indices of net protein balance and myofibrillar protein breakdown, respectively, in eight patients with cirrhosis and in 11 healthy control subjects. Whole-body protein turnover was also measured using L-[1-13C]leucine. 2. Leg efflux of tyrosine was 45% greater in cirrhotic patients than in normal control subjects [-6.5(1.4 to -19.1) vs -4.2(-2.2 to -7.7) mumol min-1 100 mg-1 of leg, median (range), P less than 0.025]. 3-Methylhistidine efflux was not significantly altered. 3. In cirrhosis, whole-body leucine flux was normal but whole-body leucine oxidation was elevated so that whole-body protein synthesis was depressed by 17%. 4. The results indicate the predominant mechanism of muscle wasting in cirrhosis to be a fall in muscle protein synthesis, which is accompanied by an overall fall in whole-body protein turnover.     

Hormone and metabolite profiles in alcoholic liver disease

Abstract. Circulating hormone and metabolite profiles have been studied in ten patients with alcoholic cirrhosis, five patients with alcoholic hepatitis and/or fatty liver, and nine normal controls over a 12-h period of meals and activity. Blood glucose was elevated throughout the day in both cirrhotic and non-cirrhotic alcoholics (mean 12-h glucose; controls 5.38 ± 0.16 (SEM) mmol/l; cirrhotics 6.98 ± 0.30 mmol/l, P < 0.001; non-cirrhotics 7.18 ± 0.26 mmol/l, P < 0.001). Non-cirrhotic alcoholics had an exaggerated insulin response to meals, whereas cirrhotic patients had hyperinsulinaemia throughout the day (mean 12-h insulin; controls 16.3 ± 2.3 mU/l; cirrhotics 35.8 ± 6.6 mU/l, P < 0.02). Growth hormone levels were elevated only in patients with cirrhosis (mean 12-h growth hormone, 7.06 ± 1.35 v. 0.85 ± 0.17 μg/l, P < 0.001). Serum Cortisol was persistently elevated in cirrhotics but only in the evening in non-cirrhotic alcoholics. Lactate and pyruvate responses to meals were exaggerated in non-cirrhotic patients whereas in cirrhotics, levels were persistently raised. Blood glycerol was elevated in all alcoholic patients whereas ketone body levels were normal. Hypertriglyceridae-mia was observed only in non-cirrhotic patients. No relationship between the endocrine and metabolic state was observed in either cirrhotic or non-cirrhotic patients.     

Glucocorticosteroid status in chronic alcoholics with and without skeletal muscle myopathy

1. Chronic alcoholism is associated with a selective atrophy of type II skeletal muscle fibres. We studied the glucocorticoid status of chronic alcoholics with and without myopathy to determine if hypercortisolism is responsible for the myopathy. 2. Twenty-four hour urinary cortisol excretion and diurnal serum cortisol measurements were not significantly different in chronic alcoholics, with and without atrophy of type II skeletal muscle fibres. 3. Diurnal serum cortisol variation was normal for both groups of alcoholics studied. None of the patients with myopathy had raised serum cortisol levels. 4. We conclude that chronic alcoholic myopathy is not due to alcohol-related pseudo-Cushing's syndrome.     

Insulin resistance in liver cirrhosis. Positron-emission tomography scan analysis of skeletal muscle glucose metabolism.

BACKGROUND. Insulin resistance and glucose intolerance are a major feature of patients with liver cirrhosis. However, site and mechanism of insulin resistance in cirrhosis are unknown. We investigated insulin-induced glucose metabolism of skeletal muscle by positron-emission tomography to identify possible defects of muscle glucose metabolism in these patients. METHODS. Whole body glucose disposal and oxidation were determined by the combined use of the euglycemic-hyperinsulinemic clamp technique (insulin infusion rate: 1 mU/kg body wt per min) and indirect calorimetry in seven patients with biopsy-proven liver cirrhosis (Child: 1A, 5B, and 1C) and five healthy volunteers. Muscle glucose uptake of the thighs was measured simultaneously by dynamic [18F]fluorodeoxyglucose positron-emission tomography scan. RESULTS. Both whole body and nonoxidative glucose disposal were significantly reduced in patients with liver cirrhosis (by 48%, P < 0.001, and 79%, P < 0.0001, respectively), whereas glucose oxidation and the increase in plasma lactate were normal. Concomitantly, skeletal muscle glucose uptake was reduced by 69% in liver cirrhosis (P < 0.003) and explained 55 or 92% of whole body glucose disposal in cirrhotics and controls, respectively. Analysis of kinetic constants using a three-compartment model further indicated reduced glucose transport (P < 0.05) but unchanged phosphorylation of glucose in patients with liver cirrhosis. CONCLUSIONS. Patients with liver cirrhosis show significant insulin resistance that is characterized by both decreased glucose transport and decreased nonoxidative glucose metabolism in skeletal muscle.     

Role of ubiquitin-proteasome pathway in skeletal muscle wasting in rats with endotoxemia

OBJECTIVE: To investigate the mechanism of muscle protein breakdown under endotoxemia condition. DESIGN: Randomized, controlled, animal experiment in a hospital institute. SETTING: Experimental laboratory. INTERVENTION: Either saline or endotoxin (Escherichia coli O(55)B(5), 10 mg/kg) were administered into the peritoneal cavity in rats. MEASUREMENTS AND MAIN RESULTS: The rate of total protein breakdown was increased by 29% and 61% in extensor digitorum longus muscle at 2 hrs and 6 hrs, whereas the myofibrillar proteolytic rate was increased by 155%, 222%, and 40% at 2 hrs, 6 hrs, and 12 hrs, respectively, in the endotoxin treatment group compared with that of the pair-fed normal control group. Meanwhile, compared with the normal control group, the level of 2.4-kilobase (kb) messenger RNA (mRNA) for ubiquitin in extensor digitorum longus muscle in rats was increased by 153% and 470% at 2 hrs and 6 hrs. There were 87% and 117% increases in 1.2-kb mRNA for E2-14K, and 89% and 168% increase in RC2 mRNA expression in extensor digitorum longus muscle in endotoxemic rats than normal control rats at 2 hrs and 6 hrs after injection of endotoxin peritoneally. The tumor necrosis factor-alpha and interleukin-6 concentrations in rat plasma progressively increased after endotoxin treatment, but tumor necrosis factor-alpha peaked at the 2-hr time point, whereas interleukin-6 peaked at 12 hrs. Endotoxin administration resulted in a marked increase in endotoxin level at 2 hrs and 6 hrs. No significant change was observed in soleus muscle after endotoxin injection. A significantly positive correlation was found between the net release of 3-methylhistidine and respective values of endotoxin, intensity of mRNA expression of 2.-kb ubiquitin, 1.2-kb E2-14K, and subunit RC2 in extensor digitorum longus muscle (r =.9882, .9731, .9653, .9814, p <.05). However, no significant correlation was seen between tumor necrosis factor-alpha or interleukin-6 and respective values of 3-methylhistidine, mRNA expression of 2.4-kb ubiquitin, 1.2-kb E2-14K, and subunit RC2 (r =.3580, .4521, .5277, .4931, p >.05; r =.3950, .1767, .2136, .2519, p >.05, respectively.) in soleus muscle. CONCLUSIONS: Endotoxemia can induce enhancement of skeletal muscle protein breakdown, mainly involving myofibrillar protein and white, fast-twitch extensor digitorum longus muscle. Ubiquitin-proteasome proteolytic pathway plays an important and major role in skeletal muscle proteolysis. Endotoxin, tumor necrosis factor-alpha, and interleukin-6 can directly or indirectly regulate muscle protein breakdown.     

Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle.

We tested the role of different intracellular proteolytic pathways in sepsis-induced muscle proteolysis. Sepsis was induced in rats by cecal ligation and puncture; controls were sham operated. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents NH4Cl, chloroquine, leupeptin, and methylamine. Ca(2+)-dependent proteolysis was determined in the absence or presence of Ca2+ or by blocking the Ca(2+)-dependent proteases calpain I and II. Energy-dependent proteolysis was determined in muscles depleted of ATP by 2-deoxyglucose and 2.4-dinitrophenol. Muscle ubiquitin mRNA and the concentrations of free and conjugated ubiquitin were determined by Northern and Western blots, respectively, to assess the role of the ATP-ubiquitin-dependent proteolytic pathway. Total and myofibrillar protein breakdown was increased during sepsis by 50 and 440%, respectively. Lysosomal and Ca(2+)-dependent proteolysis was similar in control and septic rats. In contrast, energy-dependent total and myofibrillar protein breakdown was increased by 172% and more than fourfold, respectively, in septic muscle. Ubiquitin mRNA was increased severalfold in septic muscle. The results suggest that the increase in muscle proteolysis during sepsis is due to an increase in nonlysosomal energy-dependent protein breakdown, which may involve the ubiquitin system.     

Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids.

Recent studies suggest that sepsis-induced increase in muscle proteolysis mainly reflects energy-ubiquitin-dependent protein breakdown. We tested the hypothesis that glucocorticoids activate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis. Rats underwent induction of sepsis by cecal ligation and puncture or were sham-operated and muscle protein breakdown rates were measured 16 h later. The glucocorticoid receptor antagonist RU 38486 or vehicle was administered to groups of septic and sham-operated rats. In other experiments, dexamethasone (2.5 or 10 mg/kg) was injected subcutaneously in normal rats. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Energy-dependent proteolysis was determined in incubated muscles depleted of energy with 2-deoxyglucose and 2,4-dinitrophenol. Levels of muscle ubiquitin mRNA and free and conjugated ubiquitin were determined by Northern and Western blot, respectively. RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates and blunted the increase in ubiquitin mRNA levels and free ubiquitin. Some, but not all, sepsis-induced changes in ubiquitin protein conjugates were inhibited by RU 38486. Injection of dexamethasone in normal rats increased energy-dependent proteolysis and ubiquitin mRNA levels. The results suggest that glucocorticoids regulate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis.     

Molecular mechanisms activating muscle protein degradation in chronic kidney disease and other catabolic conditions

Muscle atrophy is a prominent feature of chronic kidney disease (CKD) and is frequent in other catabolic conditions. Results from animal models of these conditions as well as patients indicate that atrophy is mainly owing to accelerated muscle proteolysis in the ubiquitin-proteasome (Ub-P'some) proteolytic system. The Ub-P'some system, however, rapidly degrades actin or myosin but cannot breakdown actomyosin or myofibrils. Consequently, another protease must initially cleave the complex structure of muscle. We identified caspase-3 as an initial and potentially rate-limiting proteolytic step that cleaves actomyosin/myofibrils to produce substrates degraded by the Ub-P'some system. In rodent models of CKD and other catabolic conditions, we find that caspase-3 is activated and cleaves actomyosin to actin, myosin and their fragments. This initial proteolytic step in muscle leaves a characteristic footprint, a 14-kDa actin band, providing a potential diagnostic tool to detect muscle catabolism. We also found that stimulation of caspase-3 activity depends on inhibition of IRS-1-associated phosphatidylinositol 3-kinase (PI3K) activity; inhibiting PI3K in muscle cells also leads to expression of a critical E3-ubiquitin-conjugating enzyme involved in muscle protein breakdown: atrogin-1/MAFbx. Thus, protein breakdown by caspase-3 and the ubiquitin-proteasome system in muscle are stimulated by the same signal: a low PI3K activity. These responses could yield therapeutic strategies to block muscle atrophy.     

Effects of Chronic Ethanol Abuse on Structure and Enzyme Activities of Skeletal Muscle in Man

Biopsies from vastus lateralis muscle of male patients suffering from chronic ethanol abuse were studied with regard to histochemical reactions of ATP-ase and NADH-diaphorase; enzymatic activities of triosephosphate dehydrogenase (TPD), lactate dehydrogenase (LD), and cytochrome c oxidase (cytox); content of ATP, creatine phosphate, and glycogen; and volume fractions of fat, mitochondria, and fibrillar and extrafibrillar space. The results were compared with those from controls without known abuse of ethanol. The relative numbers of fibers were the same in the two groups, but the size of the fast-twitch-glycolytic (white) fibers was diminished in the alcoholic group. The activities of TPD and LD were diminished in skeletal muscle of the alcoholics. This is most probably caused by the reduced amount of fast-twitch-glycolytic tissue, as there was a good correlation between this amount and the activity of the two enzymes. The activity of cytox was slightly lower in muscle of the alcoholics than in that of the controls. The volume fraction of mitochondria was lower in the alcoholic group than in the control group. Volume fractions of fat and fibrillar and extrafibrillar space were equal in the two groups. No significant differences were found in the amount of glycogen and ATP in the muscle of the two groups. However, the content of creatine phosphate is higher in the alcoholic group than in the control group.     

Decreased serum selenium m alcoholics — a consequence of liver dysfunction

The serum concentration of selenium was decreased by 17 and 48% in non-cirrhotic and cirrhotic alcoholics, respectively, as compared to healthy controls. In these alcoholics the serum selenium correlated positively with the serum albumin and plasma prothrombin time and inversely with the serum bilirubin, alkaline phosphatase and γ-glutamyi transpeptidase. Abstinence from ethanol for two weeks was without effect on the serum selenium level in non-cirrhotic alcoholics and acute alcohol intake did not change the serum selenium concentration in non-alcoholic volunteers. In patients with primary biliary cirrhosis the serum concentration of selenium was similar to that in the alcoholic cirrhotics. In patients with hypoalbuminaemia of renal origin the serum selenium was normal.

In conclusion our results show that the deterioration of liver function, irrespective of its aetiology, leads to the decrease in serum selenium levels. Whether a defect in removal of lipoperoxides is associated with this decrease in serum selenium concentration remains to be decided by further studies.     

Decreased susceptibility of red blood cells to lipid peroxidation in patients with alcoholic liver cirrhosis

Red blood cells from alcoholics with and without liver cirrhosis and control subjects were examined for the susceptibility to lipid peroxidation. Red blood cells of patients with liver cirrhosis were found to be less sensitive to hydrogen peroxide-induced peroxidation measured by a new, reliable and sensitive method: the release of pentane during red blood cell lipid peroxidation. Changes of sensitivity to lipid peroxidation correlated with the severity of the liver malfunction, but not with abnormalities of the lipid composition of red cell membranes which are apparent in patients with liver disease. In alcoholics without liver cirrhosis, only minor changes in the susceptibility of red cells to peroxidation were observed.     

The combined effects of infection and malnutrition on protein metabolism in children

Twenty-two children were studied as inpatients at a Nigerian Hospital. They were divided into four groups on the basis of weight for age: I, adequately nourished, acutely infected; II, moderately under weight, acutely infected; III, malnourished, chronically infected; IV, malnourished, uninfected. Urinary nitrogen excretion was highest in group I and lowest in groups III and IV. Urinary creatinine was highest in group I, but did not differ significantly in groups II, III and IV. The excretion of 3-methylhistidine closely paralleled that of creatinine. It is suggested that the high rates of creatinine and methylhistidine excretion in group I resulted in part from destruction of muscle. Rates of whole body protein turnover were measured by administration of a single dose of [15N]glycine with measurement of the excretion of 15N in urinary NH3 for the next 9 h. Rates of protein synthesis and breakdown were very high in infected children of groups I and II. Although rates were lower in the malnourished groups, in infected children of group III they were nearly twice as high as in the uninfected group IV. The net balance of protein (synthesis minus breakdown) was negative in group I, less negative in group II, zero in group III and positive in group IV. Repeat measurements in group I during recovery from infection showed a decline in rates of excretion of nitrogen, creatinine and 3-methylhistidine. Rates of protein synthesis and breakdown declined and the protein balance became less negative, but these changes were not statistically significant. Multiple regression analysis of the results of all groups taken together showed independent contributions to rates of protein metabolism from infection and nutritional state, especially plasma albumin. It was concluded that infection caused a rise in protein breakdown which was larger than the concomitant rise in synthesis, leading to net loss of protein, and that these responses were reduced by malnutrition.     

Exteroceptive suppression of masseter muscle activity in juvenile migraineurs

The second exteroceptive suppression period (ES2) of masseter or temporalis muscle activity may be reduced in adults with chronic tension-type headache. In adults with migraine, ES2 was found normal or tended to be protracted. To date, no studies on exteroceptive suppression in children and adolescents with headaches have been published. We investigated the exteroceptive suppression of masseter muscle activity in 14 migraineurs and 19 controls between 6 and 18 years of age. It was elicited by electrical stimulation at the labial commissure. No differences were found regarding the first suppression period, but ES2 was significantly longer in the migraine group than in controls. The results of the migraine group suggest overactivity of the interneurons of the reflex loop due to impaired inhibitory control from superior antinociceptive systems already at the beginning of this headache disorder.     

Resistance exercise effects on aging skeletal muscle in rats

The purpose of this study was to determine whether a resistance exercise program could be initiated successfully at progressively older ages in rats. Forty female Sprague-Dawley rats, 7 to 10 in each age group (21, 24, 27, and 30 months, respectively), performed 60 manually resisted chin-ups (three sets of 10 repetitions each twice daily) for three months. Twenty controls, 5 in each age group, were followed for three months but not exercised. Before the experimental period began, the rats' left palmaris longus (PL) muscle was removed, weighed, frozen, sectioned, and stained. After the three-month period, the right PL muscle was removed and the same tissue preparation procedure was followed. Muscle fiber types I and II were identified on photomicrographs, and areas of each fiber type measured. No significant change in muscle wet weight or fiber size occurred in the controls. Significant increases (p less than .01) in type II muscle fiber area occurred for the 21-, 24-, and 30-month-old rats that exercised. No histological evidence of exercise-related harm was observed in tissues from exercised rats. Results indicate that resistance exercise can be introduced successfully to an aging or aged rat without doing harm. Studies are needed to determine whether similar results can be achieved for elderly humans.