Comparison of the effects of salbutamol and clenbuterol on skeletal muscle mass and carcass composition in senescent rats.

Aging decreases skeletal muscle mass and strength, making elderly subjects particularly vulnerable to catabolic effects of age-related diseases. Clenbuterol, a muscle anabolic beta 2-adrenergic agonist, has reduced or restored skeletal muscle losses in experimental catabolic states. However, the doses of clenbuterol used to prevent or reverse muscle wasting in most animal models have exceeded the estimated safe dose in man. Recently, another beta 2-adrenergic agonist, salbuamol (albuterol), has been shown to increase muscle weight and protein content in young rats at a dose similar to that used clinically. In contrast to clenbuterol, salbutamol is currently approved for human use as a bronchodilator in the United States. This study has compared the muscle and protein anabolic effects of salbutamol at a clinically relevant dose with those of clenbuterol at a dose typically used in animal models of muscle wasting. Salbutamol and clenbuterol were administered by implanted osmotic minipumps to Fisher-344 rats aged 3 and 24 months at doses of 1.03 mg and 600 micrograms per kilogram per 24 hours for 3 weeks. The weights of five hindlimb muscles, as well as carcass protein and fat content, were determined. Salbutamol and clenbuterol increased combined hindlimb muscle weight 19% and 28% in young rats, with 19% and 25% increases in old rats. Similarly, these drugs increased gastrocnemius weight and protein content 19% and 24% in young rats, with 19% and 23% increases in old rats. Salbutamol and clenbuterol increased carcass protein content 20% and 30% in young rats, with 12% and 21% increases in old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of clenbuterol on skeletal muscle mass, body composition, and recovery from surgical stress in senescent rats.

Aging decreases skeletal muscle mass and strength, which may be exacerbated by age-related diseases. There is a need for therapeutic agents to prevent or restore loss of skeletal muscle in elderly subjects with muscle wasting disorders. Clenbuterol, a beta 2-adrenergic agonist, dramatically increases skeletal muscle mass in young animals and partially prevents or restores muscle loss in experimental models of muscle wasting. However, the protein anabolic and fat catabolic effects of clenbuterol have not been studied in senescent animals. To determine whether this drug has potential for preventing or repairing muscle loss in elderly subjects, we have examined its effects in young and old rats. Clenbuterol was administered by implanted osmotic minipumps to Fischer-344 rats ages 3, 12, and 23 months, at a dose of 1.5 mg/kg/24 h for 3 weeks. The weights of five hindlimb muscles and carcass protein and fat content were determined. Clenbuterol treatment increased the weight of skeletal muscles 22% to 39% in 3-month-old rats, 19% to 35% in 12-month-old rats, and 22% to 25% in 23-month-old animals. Likewise, clenbuterol increased carcass protein content 19% in 3-month-old rats, 16% in 12-month-old rats, and 24% in 23-month-old animals. Conversely, the drug reduced carcass fat content 36% in 3-month-old rats, 32% in 12-month-old rats, and 38% in 23-month-old rats. Therefore, clenbuterol had similar anabolic and catabolic effects in all age groups. In addition, clenbuterol stimulated recovery of skeletal muscle protein lost following pump implantation in senescent rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dietary fats on fatty acid composition and delta 5 desaturase in normal and diabetic rats.

We have studied the effect of various diets on the phospholipid fatty acid composition and in vitro delta 5 desaturase activity of hepatic microsomes derived either from the normal or streptozotocin-induced diabetic rat. The diets studied were the standard rat chow diet and a basal fat-free diet supplemented either with 20 percent saturated fat, 20 percent unsaturated fat, or 20 percent menhaden oil. Phospholipid fatty acid composition analysis revealed that the normal rat fed the saturated fat or menhaden oil diet had significantly decreased arachidonate levels, consistent with decreased delta 5 desaturase activities and decreased 18:2n-6 intake. On the contrary, the unsaturated fat diet decreased dihomo-gamma-linolenate and increased arachidonate levels, without increased delta 5 desaturase activity. Streptozotocin-induced diabetes resulted in decreased arachidonate and delta 5 desaturase activity. The unsaturated fat diet fed to the diabetic rat also failed to correct this decreased delta 5 desaturase activity. The unsaturated fatty acids in this diet also displaced a substantial amount of n-3 fatty acids in both normal and diabetic microsomes, due to the competition between these two fatty acid families for incorporation into the membrane phospholipids. Conversely, the menhaden oil diet fed to the normal and diabetic rats displaced n-6 fatty acids, reduced delta 5 desaturase activity, and enhanced 22:6n-3 incorporation into diabetic microsomes.

Altered fatty acid composition in the plasma, platelets, and aorta of the streptozotocin-induced diabetic rat.

Decreased arachidonate levels have been described in various tissues of the streptozotocin-induced diabetic rat. However, reported arachidonate changes in platelets from diabetic patients have been variable. In this communication, we describe experiments that indicate that in the short-term streptozotocin diabetic rat (2 to 3 weeks), the fatty acid composition of plasma and red blood cell lipids was altered but remained unchanged in platelet and aorta phospholipids. The altered fatty acid composition of the diabetic red blood cells and plasma cholesterol esters and phospholipids was similar to that previously found in the diabetic liver. However, in long-term diabetes (6 weeks), the phospholipid fatty acid composition of the platelet and aorta became significantly altered. Thus, in the 6-week diabetic platelet, there were increases of linoleate, dihomo-gamma-linolenate, docosapentaenoate (C22:5n-3), and docosahexaenoate, and decreases of oleate, arachidonate, and docosatetraenoate. In the aorta, there were increases of linoleate, eicosapentaenoate, and docosahexaenoate, and decreases of arachidonate, docosatetraenoate, and docosapentaenoate (C22:5n-6). Results from these experiments indicate that the fatty acid composition of plasma and red blood cell lipids was altered in short-term diabetes (2 to 3 weeks), but that of platelet and aorta phospholipids was not changed until more prolonged diabetes was present. Insulin treatment of the diabetic rat increased the levels of palmitoleate and oleate and decreased the levels of linoleate in platelet and aorta lipids from insulin-treated diabetic rats, suggesting an overcorrection of diminished delta 9 and delta 6 fatty acid desaturation as compared with the nondiabetic control.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effect of a protein-free and restricted high protein-low carbohydrate diet on ventricular myosin ATPase activity and isomyosin profile in young rats: evidence that protein-depleted animals are euthyroid.

Young rats fed a protein-deficient diet have elevated total triiodothyronine (T3) levels in spite of decreased skeletal muscle protein turnover. Interpretation of the thyroid status of these animals is complicated by increased T3 binding by serum proteins. Free T3 levels ranging from normal to low and decreased resting oxygen consumption have been reported. To investigate the thyroid status of animals fed a protein-free diet, ventricular myosin ATPase activity and isomyosin profile have been used as an index of thyroid hormone activity. The effect of the protein-free diet has been compared to a restricted high protein-low carbohydrate diet, which causes clear evidence of decreased thyroid hormone effect. After 28 d, calcium-activated myosin ATPase activity was 1.50 +/- 0.05 mumol Pi/(mg protein.min) in animals fed the basal diet, 1.16 +/- 0.03 mumol Pi/(mg protein.min) in animals fed the restricted high protein-low carbohydrate diet and 1.48 +/- 0.04 mumol Pi/(mg protein.min) in animals fed the protein-free diet. In addition, a shift in isomyosin content with the appearance of V2 and V3 isomyosins occurred with the restricted high protein-low carbohydrate diet but not the protein-free diet. The failure of the protein-depleted rats to decrease myosin ATPase activity and alter isomyosin content suggests that they are euthyroid.

Effect of graded doses of tri-iodothyronine on ventricular myosin ATPase activity and isomyosin profile in young and old rats.

Ventricular myosin ATPase activity, V1 isomyosin content and serum T3 (tri-iodothyronine) values decrease with age in male Fischer 344 rats. To determine if the age decrement in ATPase activity and V1 isomyosin content are caused by decreased T3 levels or an age-related decrease in V1 isomyosin induction by T3, 3-, 12- and 24-month-old male Fischer 344 rats were given constant T3 infusions by osmotic minipump. Rats at all ages were given 0.75, 5 and 15 micrograms(/100 g per 24 h) doses of T3, whereas 12- and 24-month-old rats were given an additional 0.4 microgram dose. In control rats, T3 levels decreased from 97 +/- 2.7 at 3 months to 75 +/- 4.7 ng/100 ml at 24 months. Likewise, Ca2+-activated myosin ATPase activity decreased from 1.04 +/- 0.05 to 0.68 +/- 0.05 mumol of Pi/min per mg of protein, and the relative proportion of V1 of isomyosin decreased from 90 +/- 4.0 to 26 +/- 2.0%. The lowest (0.4 microgram) T3 dose, which was sufficient to restore T3 levels in 24-month-old animals to 3-month control values, abolished the age decrement in myosin ATPase activity and markedly increased the proportion of V1 isomyosin present in the ventricle. These findings indicate that the senescent ventricle responds readily to small doses of T3 and strongly suggest that the age decrement in serum T3 levels is sufficient to contribute to the age-related decrease in myosin ATPase activity and V1 isomyosin content. Since these parameters correlate with ventricular contractility, the age decrement in T3 levels may also contribute to the decreased ventricular contractility and cardiac output observed in senescent rats.