Mitochondrial myopathy in rats fed with a diet containing beta-guanidine propionic acid, an inhibitor of creatine entry in muscle cells.

In rats with phosphoryl-creatine depletion (fed a standard Randoin-Causeret diet containing 1% beta-guanidine propionic acid) abnormal mitochondria were observed in slow skeletal muscles, often containing paracrystalline inclusions very like those induced by ischaemia or mitochondrial poisons and in human mitochondrial myopathy

Effects of the administration of angiotensin II on cardiac glycogen metabolism in the rat.

Changes in glycogen metabolism after an intravenous injection of angiotensin II were investigated in the left and right ventricles of the rat heart, as a function of location within the ventricular wall. Hearts were cut into 100-microns thin section, all of which were analysed for glycogen content, glucose incorporation into glycogen and 2-deoxyglucose uptake and phosphorylation after the intravenous injection of 14C-labelled sugar. In control hearts, glycogen levels were uniform across the wall in both ventricles, while the rate of sugar uptake and phosphorylation, and that of glucose incorporation into glycogen, were significantly higher in the subendocardial myocardium of the left ventricular wall. After angiotensin II administration, heart glycogen levels decreased slightly in the left, but not in the right ventricle, while 2-deoxyglucose uptake and phosphorylation, and glucose incorporation into glycogen, increased 2,5- and 5-fold, respectively. With regard to the distribution across the wall of the left ventricle after angiotensin administration, glycogen levels and glucose incorporation into glycogen were uniformly distributed, whereas sugar phosphorylation was still higher in the subendocardium

Transmural gradient of glycogen metabolism in the normal rat left ventricle.

The changes of glycogen metabolism with the location of tissue within the ventricle wall have been explored in the rat myocardium. The hearts were cut in 100 microns thick serial sections and all sections were analyzed for their content in glycogen, glucose-6-phosphate, UDPG and glycogen enzymes and for glucose incorporation into glycogen and for the 2-deoxyglucose uptake after the intravenous injection of the 14C-labelled sugars. The rate of glycogen turnover was significantly higher in the subendocardial myocardium (P less than 0.01) and the levels of glucose-6-phosphate and the total (i.e. a + b) activity of glycogen phosphorylase were significantly higher in the subepicardial tissue (P less than 0.01 in both instances). No significant transmural gradient of UDPG was found and transmural changes of total (i.e. I + D) synthase activity were barely significant. These changes in glycogen metabolism may be related to regional differences in the cardiac work load and to a differentiation of the subendocardial and subepicardial heart fibers

ENDOCRINE AND AMINO-ACID REGULATION OF LIVER MACROAUTOPHAGY AND PROTEOLYTIC FUNCTION

Endocrine and amino acid regulation of liver macroautophagy and proteolytic function. Am, J. Physiol. 266 (Gastrointest. Liver Physiol. 29): G118-G122, 1994.-Regulation of liver macroautophagy and protein degradation by hormones and direct regulatory amino acids were studied in male 2-mo-old Sprague-Dawley albino rats with the use of the antilipolytic agent 3,5'-dimethylpyrazole (DMP; 12 mg/kg body wt ip) as a stimulatory agent. Injection of DMP decreased glutamine plasma levels and glutamine release from the perfused liver. Autophagic vacuoles were observed in the pericanalicular area of liver cells after 30 min. Levels and release of other regulatory amino acids did not exhibit any significant decrease but subsequently increased. Intraperitoneal administration of glutamine inhibited the proteolytic response. In conclusion, these studies demonstrate that in vivo induction and control of liver macroautophagy and protein degradation by the physiological mechanism (i.e., by shortage of nutrients) involve unbalanced and asynchronous changes in the levels of selected direct regulatory amino acids (i.e., a decrease in glutamine and a subsequent increase in leucine and tyrosine levels)

Transmural distribution of hexokinase, glucose-6-phosphate dehydrogenase and glutamate-oxalacetate transaminase in the left ventricle of the rat

The changes in hexokinase (HK), glucose-6-phosphate dehydrogenase (G6P-DH) and glutamate aspertate aminotransferase (GOT) activities with the location of tissue within the left ventricle wall have been explored in the rat myocardium. The hearts were cut in 100 micron thick serial sections (see 4) and all sections spectrophotometric procedures (5). No significant transmural gradient in HK activity was observed but the levels of G6P-DH and of GOT activities were significantly higher in the subepicardial tissue and were at their lowest levels in the midmyocardial layers. Our data and previous observations (3,6) indicate that adptions to regional differences in the cardiac work load occurred in the left ventricle wall but that the transmural patterns of enzyme distribution may change with the different animal specie

Regional differences in the response of cardiac cells to triiodothyronine administration across the left ventricle free wall of rat heart.

We have studied the effect of T3 administration (50 micrograms/Kg/day) on the phenotype expression of several glucose-metabolizing enzymes (hexokinase, HK, glucose-6-phosphate dehydrogenase, G6P-DH, aldolase, ALD, phosphofructokinase, PFK, lactate dehydrogenase, LDH) in the different myocardial layers of the left ventricle wall. In the control rats, most of these enzyme activities are uniformly distributed across the left ventricle wall, G6P-DH being the only exception. In the rats given T3 for 14 days, the mean levels of PFK, HK and ALD activities increased significantly. With regard to the transmural distribution patterns, that of PFK was unchanged, unlike those of HK and ALD which exhibited their maximum increase in activity in the midmyocardium or in the mid- and subepicardial myocardium. With LDH, a significant increase in activity was found in the subepicardial layers which escaped detection on the whole homogenate. It is concluded that the administration of thyroid hormone has different effects on enzyme phenotype expression of cardiomyocytes in different regions of the cardiac wall

The anti-ageing effects of caloric restriction may involve stimulation of macro autophagy and lysosomal degradation, and can be intensified pharmacologically

Caloric restriction (CR) and a reduced growth hormone (GH)-insulin-like growth factor (IGF-1) axis are associated with an extension of lifespan across taxa. Evidence is reviewed showing that CR and reduced insulin of GH-IGF-1 axis may exhibit their effects at least partly by their common stimulatory action on autophagy, the cell repair mechanism responsible for the housekeeping of cell membranes and organelles including the free radical generators peroxisomes and mitochondria. It is shown that the life-long weekly administration of an anti-lipolytic drug may decrease glucose and insulin levels and stimulate autophagy and intensify anti-ageing effects of submaximal CR

Evidence that autophagy is involved in aging and is an essential in the anti-aging mechanism of caloric restriction

Aging denotes a postmaturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes of this deterioration may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and incomplete "housekeeping." Caloric restriction is the most robust anti-aging intervention known so far. Similar beneficial effects on median and maximum life span were obtained by feeding animals a 40%-reduced diet or by every-other-day ad libitum feeding. In both instances, animals are forced to spend a great part of their time in a state of fasting and activated autophagy. Autophagy is a highly conserved process in eukaryotes, in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the lysosome/vacuole, for breakdown and eventual recycling of the resulting macromolecules. This process has an essential role in adaptation to fasting and changing environmental conditions, cellular remodeling during development, and accumulation of altered ROS-hypergenerating organelles in older cells. Several pieces of evidence show that autophagy is involved in aging and is an essential part of the anti-aging mechanism of caloric restriction. As an application, intensification of autophagy by the administration of an antilipolytic drug rescued older cells from accumulation of altered mtDNA in less than 6 hours. It is concluded that the pharmacologic intensification of autophagy (PISA treatment) has anti-aging effects and might prove to be a big step toward retardation of aging and prevention of age-associated diseases in human

Transmural distribution of glucose metabolizing enzymes across the left and the right ventricle heart walls in three different mammalian species.

The transmural distribution of five glucose metabolizing enzymes (hexokinase; glucose-6-phosphate dehydrogenase; phosphofructokinase; aldolase; and lactate dehydrogenase) were explored in the left and in the right ventricle wall of rat, ox and pig hearts. The levels of most of these enzyme activities were different in the different animal species and (within the same species) in the two ventricles. Most of these enzyme activities were found to be non-uniformly distributed across the left (but not across the right) ventricle wall. Differences in the transmural distribution of enzyme activities were detected among the three examined mammalian species

Metabolic heterogeneity of the muscle tissue: transmural distribution of glucose metabolizing enzymes across the left ventricular wall of control and hypertrophic rat heart.

Mammalian cardiac muscle is a remarkably heterogeneous tissue, as judged from enzyme analysis of tissue from different myocardial layers of the left ventricle free-wall. Its diversity results from a spectrum of fibres with different metabolic properties and different location across the wall, which may be especially suited to the local range of functional demands