The molecular origin of standard metabolic rate and thermogenesis in mammals is examined. It is pointed out that there are important differences and distinctions between the cellular reactions that 1) couple to oxygen consumption, 2) uncouple metabolism, 3) hydrolyze ATP, 4) control metabolic rate, 5) regulate metabolic rate, 6) produce heat, and 7) dissipate free energy. The quantitative contribution of different cellular reactions to these processes is assessed in mammals. We estimate that approximately 90% of mammalian oxygen consumption in the standard state is mitochondrial, of which approximately 20% is uncoupled by the mitochondrial proton leak and 80% is coupled to ATP synthesis. The consequences of the significant contribution of proton leak to standard metabolic rate for tissue P-to-O ratio, heat production, and free energy dissipation by oxidative phosphorylation and the estimated contribution of ATP-consuming processes to tissue oxygen consumption rate are discussed. Of the 80% of oxygen consumption coupled to ATP synthesis, approximately 25-30% is used by protein synthesis, 19-28% by the Na(+)-K(+)-ATPase, 4-8% by the Ca2(+)-ATPase, 2-8% by the actinomyosin ATPase, 7-10% by gluconeogenesis, and 3% by ureagenesis, with mRNA synthesis and substrate cycling also making significant contributions. The main cellular reactions that uncouple standard energy metabolism are the Na+, K+, H+, and Ca2+ channels and leaks of cell membranes and protein breakdown. Cellular metabolic rate is controlled by a number of processes including metabolic demand and substrate supply. The differences in standard metabolic rate between animals of different body mass and phylogeny appear to be due to proportionate changes in the whole of energy metabolism. Heat is produced by some reactions and taken up by others but is mainly produced by the reactions of mitochondrial respiration, oxidative phosphorylation, and proton leak on the inner mitochondrial membrane. Free energy is dissipated by all cellular reactions, but the major contributions are by the ATP-utilizing reactions and the uncoupling reactions. The functions and evolutionary significance of standard metabolic rate are discussed.

Cellular energy utilization and molecular origin of standard metabolic rate in mammals

PERSPECTIVES AND OVERVIEW . . . . . . . . . . . . . . . . . . 748 INTRODUCTION ....... 749 SELECTIVITY OF INTRACELLULAR PROTEIN DEGRADATION 749 Selectivity of the Degradative Process in Mammalian Cells 749 Biochemical Basis of Selectivity 752 Degradation of Abnormal Proteins in Mammalian Cells 755 Aging and the Degradation of Abnormal Proteins 758 Selectivity 0/ the Degradative Process in E. coli 760 Degradation of Abnormal Proteins in E. coli 762 E. coli MUlants De/ee/ive in Pro/ein Degradation 766 CONTROL OF THE OVERALL RATES OF PROTEIN DEGRADATION 767 Regulation of Proteolysis in E. coli 767 Mechanisms Regulating Protein Degradation and RNA Synthesis in E. coli 773 Regulation of Pratein Degradation in Mammalian Cells .. ....... ....... 775 Protein Degradation and Control of Cell Growth 776 Protein Degradation in Mammalian Tissues upon Deprivation of Nutrients 780 BIOCHEMICAL CONSIDERATIONS . . . .. ......... 783 Effects uf Inhibitors uf Protein Synthesis on Protein Degradation 783 Energy Requirement for Protein Degradation 787 The E nzymes Responsible lor Protein Degradation ........ ......... ........ 791

Intracellular Protein Degradation in Mammalian and Bacterial Cells: Part 2

mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1KO) reduces muscle mass. PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity.

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PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase.

The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.

Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading

The speed of absorption of dietary amino acids by the gut varies according to the type of ingested dietary protein. This could affect postprandial protein synthesis, breakdown, and deposition. To test this hypothesis, two intrinsically 13C-leucine-labeled milk proteins, casein (CAS) and whey protein (WP), of different physicochemical properties were ingested as one single meal by healthy adults. Postprandial whole body leucine kinetics were assessed by using a dual tracer methodology. WP induced a dramatic but short increase of plasma amino acids. CAS induced a prolonged plateau of moderate hyperaminoacidemia, probably because of a slow gastric emptying. Whole body protein breakdown was inhibited by 34% after CAS ingestion but not after WP ingestion. Postprandial protein synthesis was stimulated by 68% with the WP meal and to a lesser extent (+31%) with the CAS meal. Postprandial whole body leucine oxidation over 7 h was lower with CAS (272 +/- 91 micromol.kg-1) than with WP (373 +/- 56 micromol.kg-1). Leucine intake was identical in both meals (380 micromol.kg-1). Therefore, net leucine balance over the 7 h after the meal was more positive with CAS than with WP (P < 0.05, WP vs. CAS). In conclusion, the speed of protein digestion and amino acid absorption from the gut has a major effect on whole body protein anabolism after one single meal. By analogy with carbohydrate metabolism, slow and fast proteins modulate the postprandial metabolic response, a concept to be applied to wasting situations.

https://www.pnas.org/content/pnas/94/26/14930.full.pdf

Slow and fast dietary proteins differently modulate postprandial protein accretion

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Protein turnover in mammalian tissues and in the whole body

1. Measurements have been made of whole-body and skeletal muscle protein synthesis in fed and fasted adults with L-[1-13C]leucine. 2. The marked increase in whole-body synthesis on feeding largely reflects the changes in protein synthesis in muscle, which doubles on feeding, compared with a 40% increase in that of the rest of the body. 3. Skeletal muscle in fed man contributes more than half to total protein synthesis occurring in the whole body.

Muscle protein synthesis measured by stable isotope techniques in man: the effects of feeding and fasting.

1. The rate of protein synthesis in rat tissues was measured by constant intravenous infusion of [14C]tyrosine. A modification has been developed for the method of calculating the rate of protein synthesis in individual tissues from the specific radioactivity of the free and protein-bound amino acid in tissue at the end of the infusion. This technique gives greater accuracy and allows a greater choice of labelled amino acids. The specific radioactivity of free tyrosine in plasma was used to calculate the plasma tyrosine flux, an index of the rate of protein synthesis in the whole body. 2. Young male Wistar rats were allowed access to food for only 4h in every 24h. The tyrosine flux and the rate of protein synthesis in liver and muscle at different periods of time after a single feed were estimated. 3. The tyrosine flux did not alter after feeding nor even after starvation for 48h. 4. The average fractional rate of protein synthesis in muscle was 7.2%/day, i.e. the proportion of the protein mass which is replaced each day. The rate rose after eating and declined during starvation for 48h. In addition the rate of muscle protein synthesis correlated with the growth rate of the rat. 5. In liver the average fractional rate of protein synthesis was 50%/day. There was no change in the rate after eating nor after starvation for 48h. In contrast with muscle this suggests that the changes in protein mass were accompanied by changes in the rate of protein breakdown rather than synthesis.

The diurnal response of muscle and liver protein synthesis in vivo in meal-fed rats.

Because of turnover, protein synthesis and breakdown can each be involved in the regulation of the growth of tissue protein. To investigate the regulation of skeletal-muscle-protein growth we measured rates of protein synthesis and breakdown in growing rats during development on a good diet, during development on a marginally low-protein diet and during rehabilitation on a good diet after a period of severe protein deficiency. Rates of protein synthesis were measured in vivo with a constant intravenous infusion of [14C]tyrosine. The growth rate of muscle protein was measured and the rate of breakdown calculated as breakdown rate=synthesis rate-growth rate. These measurements showed that during development on a good diet there was a fall with age in the rate of protein synthesis resulting from a fall in capacity (RNA concentration) and activity (synthesis rate per unit of RNA). There was a fall with age in the breakdown rate so that the rate was highest in the weaning rats, with a half-life of 3 days. There was a direct correlation between the fractional growth and breakdown rates. During rehabilitation on the good diet, rapid growth was also accompanied by high rates of protein breakdown. During growth on the inadequate diet protein synthesis rates were lesss than in controls, but growth occurred because of decreased rates of protein breakdown. This compression was not complete, however, since ultimate muscle size was only one-half that of controls. It is suggested that increased rates of protein breakdown are a necessary accompaniment to muscle growth and may result from the way in which myofibrils proliferate.

Skeletal-muscle growth and protein turnover.

The effects of growth-suppressing and muscle-wasting treatments on muscle protein turnover and amino acid concentrations were determined in vivo. All treatments depressed protein synthesis and some treatments depressed protein breakdown. Only prolonged starvation increased protein breakdown. Muscle protein mass is regulated primarily through alterations in protein synthesis in all except emergency conditions. The increased concentrations of the branched-chain amino acids indicate that they are unlikely to be involved in this regulation.

David J. Millward

Papers

Protein turnover in mammalian tissues and in the whole body

Muscle protein synthesis measured by stable isotope techniques in man: the effects of feeding and fasting.

The diurnal response of muscle and liver protein synthesis in vivo in meal-fed rats.

Skeletal-muscle growth and protein turnover.

The relative importance of muscle protein synthesis and breakdown in the regulation of muscle mass.