Biochemical Foundations of Human Vital Activity - Volkov, N. I., Nesen, E. N. 2000

Biochemical Foundations of Human Vital Activity
Integration and Regulation of Metabolism as the Biochemical Basis of Adaptation Processes
Regulatory Systems of Metabolism and Their Role in the Adaptation of the Organism to Physical Exertion

The rate of METABOLISM in The Human Body is determined by hereditary factors and regulated by various control systems. There are three main systems regulating metabolism: intracellular (autoregulation), hormonal, and neural (Fig. 103). Under their influence, the amount and activity of Enzymes, Coenzymes, and substrates change, ensuring the necessary rate and direction of biochemical processes. These systems govern the mechanisms of the body's general adaptation to physical exertion and other stimuli, as well as the adaptive restructuring of metabolism during systematic physical exertion (training).

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Fig. 103 Diagram of Metabolic Regulation

Intracellular Regulatory System

Metabolism at the cellular and subcellular levels is regulated primarily by altering The activity of existing cellular enzymes or changing their quantity.

Introduction/15.html">Regulation of enzyme Activity. Enzyme activity can be influenced by many factors, in particular the concentration of substrate and coenzyme, the presence of activators and inhibitors, medium pH, Temperature, aqueous environment, the state of Biological Membranes, and the chemical Modification of the Enzyme Structure through phosphorylation, proteolysis, etc. The simplest regulatory mechanism involves substrate and coenzyme concentrations. If an enzyme operates within the substrate half-saturation range, even minor changes in its concentration can lead to a significant shift in the rate of the biochemical reaction. Changes in the concentrations of coenzymes NAD, NADP, FAD, CoA, etc., as well as the Vitamins that comprise them, also affect the Rate of Enzymatic reactions. The variety of enzymatic processes whose rates depend on the presence of vitamins is illustrated in Fig. 104.

A rapid and "fine-tuned" mechanism is the so-called Allosteric Regulation of enzyme activity by substances that bind to the allosteric site of the enzyme and alter its conformation. Typically, such an enzyme is located at the beginning of a metabolic pathway. However, it can be inhibited by the end product of that metabolism upon its accumulation, or by several metabolites acting as its Allosteric regulators. A prime example is the key glycolytic enzyme Phosphofructokinase (PFK), which has about 10 allosteric regulators that interact with it to alter its activity. These substances include ATP, ADP, AMP, Pi, citric acid, Fatty acids, as well as pH and other factors. In a state of relative rest, PFK in skeletal Muscles is inactive because it is inhibited by high concentrations of ATP and citric acid. During intense muscular activity, the concentration of ATP decreases, while the concentrations of ADP and AMP increase. This activates PFK and accelerates Glycolysis. When the ATP balance in the muscles is restored—which occurs when oxygen supply improves—PFK activity decreases, and the rate of glycolysis drops. Muscles then switch to the Aerobic Mechanism of energy production with a gradual transition to fat utilization.

A common method of regulating enzyme activity involves the modification of enzyme protein molecules through phosphorylation-dephosphorylation, proteolytic Cleavage of a protein segment, or other influences. The activity of tissue lipases (which break down neutral fats) and phosphorylase (which breaks down Glycogen) is regulated via phosphorylation involving ATP and Mg²⁺, as well as dephosphorylation catalyzed by enzymes (Phosphatases) (Fig. 105). Often, processes of enzyme phosphorylation-dephosphorylation in the Cell Cytoplasm are linked to hormonal regulation via cAMP, Ca²⁺, or other hormone second messengers.

Fig. 104 Effect of Water-Soluble Vitamins on carbohydrate, lipid, and Amino acid metabolism

Fig. 105 REGULATION OF CARBOHYDRATE and Lipid Metabolism enzyme activity via cAMP-dependent phosphorylation of their molecules

The aforementioned mechanisms of ENZYME ACTIVITY REGULATION are capable of altering metabolic rates very quickly—within seconds or minutes—and belong to the mechanisms of immediate metabolic regulation. They activate energy and other processes during muscular activity.

Regulation of Enzyme Synthesis. In living Cells, the relative constancy of protein levels, including so-called constitutive enzymes, is programmed at the level of the genetic apparatus. However, changes in Nutrition, prolonged fasting, or athletic training can alter the amounts of specific Proteins. There is adaptive control of Protein Biosynthesis at the level of individual genes, which induces (enhances) or represses (reduces) the rate of RNA Synthesis. Inducers or repressors can be enzyme substrates or the products of a given reaction. The Induction of the synthesis of a specific enzyme leads to its accumulation when the concentration of its substrate increases or when There is a need to increase its metabolic rate. Repression occurs when the substrate is absent and the enzyme is no longer needed, or when The Cell is conserving its energy resources.

Regulation of enzyme synthesis at the cellular genetic level can lead to an increase or decrease in The amount of the enzyme, A change in the cell's enzymatic composition, or the appearance of new enzyme isoforms. Such regulation occurs relatively slowly—from several hours to several days—and is considered "coarse" metabolic regulation. It plays a major role in the long-term adaptation of the body's metabolism to physical exertion.

Many inherited Metabolic Disorders are associated with alterations in genes (Mutations) that encode enzyme synthesis or the adaptive control system. This leads to changes in enzyme quantity and activity, which causes altered rates of metabolic reactions, the accumulation of metabolic products or substrates, and The Development of specific pathologies.

During the body's adaptation to various environmental factors, or in the presence of diseases, the Regulation of the isoenzyme spectrum of individual enzymes changes. The appearance of new enzyme isoforms can serve as a diagnostic indicator of adaptive changes at the level of Protein Synthesis processes or the development of a specific disease.

In addition to substrates, many metabolites and Hormones influence enzyme biosynthesis processes at the genetic level. A major role in inducing adaptive protein synthesis during muscular activity and training is played by a deficit of ATP and creatine phosphate, as well as hormones such as glucocorticosteroids, thyroxine, Insulin, somatotropin, and androgens, which exhibit adaptive anabolic effects. As shown in the works of A.A. Viru and colleagues, the regulatory effect of these hormones on genome activity and protein synthesis underlies the transition of immediate adaptive responses in the athlete's body into long-term adaptation.

Hormonal Regulation

Metabolism is regulated by hormones secreted into the Blood by Endocrine glands. The Role of individual hormones in metabolic regulation was examined in Chapter 8. Here, we will focus in greater detail on the GENERAL PATTERNS OF hormonal regulation during the adaptive restructuring of metabolism associated with muscular activity.

The endocrine gland responds to various stimuli by increasing or decreasing the release of hormones into the bloodstream relative to its baseline level:

During muscular activity, the levels of individual hormones can change in opposite directions depending on the intensity of physical exertion and the functional state of the body. Under intense muscular activity, the activity of many endocrine glands increases, particularly those whose hormones regulate the mobilization, oxidation, and recovery of Energy Sources. As a result, the concentrations of noradrenaline and adrenaline (which is 5–10 times more active than noradrenaline), Glucagon, glucocorticosteroids, and Growth Hormone in the blood increase. However, insulin concentration most often decreases. These hormones participate in the Regulation of Blood glucose concentration in the following manner:

A decrease in insulin concentration during physical exertion reduces glucose uptake by Tissues and helps elevate its blood levels, whereas an increase in the concentration of insulin antagonists (glucagon, adrenaline, cortisol, somatotropin) raises blood glucose by mobilizing it from the Liver or activating Gluconeogenesis. Changes in The ratio of these hormones affect metabolic processes in working muscles and other tissues.

According to H. Selye's theory, pituitary and Adrenal hormones play the most critical role in the body's adaptation to stressors, including intense physical exertion. The Development of the so-called General adaptation syndrome is controlled by the Hypothalamus. The hypothalamus integrates information received from all PARTS OF THE body, including the Central Nervous system, and triggers hormonal mechanisms to maintain relative metabolic Homeostasis (Fig. 106). First and foremost, the secretion of catecholamines—adrenaline and noradrenaline—by The adrenal medulla is amplified. They activate Glycogenolysis in The Liver and elevate blood glucose levels, as well as promote lipid breakdown; in other words, they mobilize the body's energy reserves and enhance the energy supply to Organs and tissues. Subsequently, as the concentration of catecholamines in the blood rises, pituitary synthesis of ACTH is stimulated, which in turn activates the synthesis of glucocorticosteroids (cortisol) in the adrenal cortex. Cortisol initiates adaptive enzyme synthesis reactions, stimulates hepatic gluconeogenesis from non-carbohydrate precursors and fat mobilization, and concurrently reduces tissue protein synthesis, leading to an increased pool of Amino Acids required for adaptive substance synthesis. All of this creates optimal conditions for maintaining a high rate of energy production under conditions of elevated tissue energy demands. During stress, adrenaline and corticosteroids act synergistically to ensure a high rate of Catabolism of mobilized energy sources, which is why these hormones are termed adaptive.

Fig. 106. The role of pituitary and adrenal hormones in mediating the body's general adaptation to stress

Under stressful conditions, the secretion of Other Hormones—such as glucagon, growth hormone, and vasopressin—is also activated. They further enhance the mobilization of energy resources, both CARBOHYDRATES and fats. Growth hormone stimulates overall protein synthesis, leading to hypertrophy (an increase in mass) of the Adrenal Glands, and, in the case of systematic physical training, hypertrophy of skeletal muscles and the myocardium as well. Adrenal hypertrophy enhances their secretory capacity. Elevated blood concentrations of catecholamines and glucocorticosteroids during prolonged physical exertion contribute to improved athletic performance. Stressful stimuli also elevate vasopressin levels, which regulate water-salt balance by reducing urine output and expanding Blood Plasma volume, which is essential for maintaining blood pressure and cardiovascular function. Thus, the Endocrine System orchestrates adaptive metabolic shifts in response to environmental changes.

In a trained Organism, the endocrine gland response to physical exertion is altered. In athletes specializing in endurance sports, physical loads do not elicit significant spikes in blood concentrations of adrenaline, glucagon, somatotropin, and cortisol, while insulin levels drop to a lesser degree. Such hormonal adaptation to training likely reflects metabolic plasticity. It develops quite rapidly (within just a few weeks) and persists even after five weeks of detraining.

Fig. 107. Mechanisms of signal Transduction for hormonal action on intracellular processes

During The process of adaptation to physical exertion, an increased sensitivity of cells to hormones and neurohormones is observed. This can induce various alterations in the regulated organ, as there are multiple types of hormone-receptor interactions and pathways transmitting their influence to intracellular processes. As illustrated in Fig. 107, the binding of a hormone to a receptor located on the outer surface of the cell's Plasma Membrane can trigger various Conformational Changes in the membrane, resulting in:

✵ the opening of Ion Channels in nerve and Muscle Tissues, altering the Membrane Potential and intracellular ion concentrations;

✵ the activation of the enzyme Tyrosine kinase by insulin, which enhances PROTEIN SYNTHESIS AND enzyme phosphorylation processes;

✵ the activation of adenylate cyclase, which catalyzes cAMP synthesis and cAMP-mediated processes;

✵ The production of Inositol trisphosphate or diacylglycerol, which regulate the rate of phosphorylation processes or intracellular free calcium levels.

Animal experiments have demonstrated an increased sensitivity of cAMP-dependent protein Kinases to cAMP as a secondary messenger for certain hormones in skeletal muscles following prolonged Physical Exercise. This may indicate the possibility of finer regulation of intracellular processes during minor fluctuations in blood hormone levels, which is characteristic of a trained organism. Consequently, during adaptation to physical loads, the hormonal system becomes more economical, creating the conditions for the efficient utilization of energy reserves and a more effective energy supply for muscular activity.

Fig. 108. Schematic diagram of the Hormonal Regulation of ATP production in Mitochondria

The mechanisms of hormonal control over intracellular processes are quite complex, as evidenced by the recently elucidated hormonal control of ATP production during Oxidative Phosphorylation in adipose tissue mitochondria, shown in Fig. 108. The Mechanism of hormonal activation of mitochondrial ATP synthesis includes:

✵ binding of the hormone noradrenaline to a receptor on the outer cell membrane;

✵ activation of adenylate cyclase, which synthesizes cAMP from ATP;

✵ binding of cAMP to cAMP-dependent protein kinase, resulting in its activation;

✵ cAMP-dependent phosphorylation of hormone-sensitive lipase, which breaks down triglycerides;

✵ opening of a blocked channel in the mitochondrial membrane through which hydrogen protons (H⁺) enter the mitochondrial matrix;

✵ activation of ATP synthase by H⁺ protons, leading to ATP synthesis.

The Nervous Regulation System

The Nervous System plays a vital role in integrating and regulating biochemical processes at the organismal level: the central nervous system continuously informs organs and tissues about environmental stimuli and coordinates their metabolism, preparing the body for muscular activity or short-term metabolic stress. The nervous system comprises approximately 10¹⁰ Nerve Cells, or Neurons, which are capable of receiving, conducting, and transmitting signals. Neurons consist primarily of three parts: the cell body, dendrites (which receive signals), and the axon—a cellular process that transmits signals to target organs (Fig. 109, a). An axon can branch and simultaneously transmit a signal to numerous cells. Nerve cells that regulate Muscle contraction are called motor neurons.

The length of a motor neuron axon, such as one innervating the Muscles of the FOOT, can reach up to 1 meter. However, nerve impulses are transmitted extremely rapidly. The propagation velocity can reach 100 m ⋅ s^-1. This is accomplished through the action of Na⁺-K⁺-ATPase, which pumps Na⁺ out of the cell in exchange for K⁺ using energy derived from ATP, thereby generating an electrical potential gradient (Fig. 109, b).

The resting membrane potential of an axon is maintained at around — 70 mV. An Action Potential is generated by a rapid influx of Na⁺ ions from the extracellular space into the nerve terminal, triggered by the selective opening of Na⁺ channels in the membrane upon neural stimulation. Simultaneously, the membrane permeability to K⁺ ions increases, causing them to flow out of the nerve fiber. The Resting Potential is restored as Na⁺ ions are pumped out and K⁺ ions are pumped back in by the action of membrane-bound Na⁺-K⁺-ATPase (see Fig. 109, b).

Nerve impulses are transmitted to other cells via specialized structures known as synapses. Synapses are the junction sites where a nerve terminal meets the surface membrane of a target cell. They comprise the presynaptic membrane, the postsynaptic membrane, and the synaptic cleft (Fig. 110). Synapses are classified into Electrical and Chemical types. In chemical synapses, Nerve Impulse transmission relies on Neurotransmitters. These chemical messengers include acetylcholine, adrenaline, noradrenaline, as well as dopamine, serotonin, glutamic acid, Glycine, GABA, and others. Synapses are adapted for the rapid release of neurotransmitters, which are synthesized in efferent neurons and stored in synaptic vesicles. Consequently, the nervous system exerts a rapid effect on a relatively restricted area of an organ. Since skeletal muscles are regulated by chemical synapses involving the neurotransmitter acetylcholine, let us examine how this regulatory control is achieved.

Fig. 109 Structure of a neuron (a) and the generation of an action potential along the axon (b)

Acetylcholine is synthesized from acetyl-CoA and Choline within nerve endings through the catalytic action of the enzyme choline acetyltransferase:

During nerve impulse transmission, Acetylcholine is released into the synaptic cleft, where it binds to specific receptors on the postsynaptic membrane of the effector organ (see Fig. 110). Acetylcholine triggers Ion transport across the membrane and a cascade of biochemical reactions that drive the specific Functions of the organ. Within milliseconds of the cessation of the nerve impulse, acetylcholine is hydrolyzed by the enzyme acetylcholinesterase into acetate and choline, thereby terminating its neurotransmitter action:

In this way, the nervous system regulates and integrates numerous processes across organs and tissues, ensuring optimal body function under various internal and external stimuli. Disruptions in neural regulation (denervation) alter the intensity and direction of metabolism in the target organ, potentially leading to pathological functional changes.

Fig. 110 Main functional components of a synapse

During motor activity, the contraction of skeletal muscles is regulated by the nervous system. This regulatory control can manifest in the following ways:

✵ recruiting varying numbers of muscle fibers (motor units) into contraction;

✵ altering the frequency of innervation or activation of motor units;

✵ engaging motor neurons of different sizes—small ones with low excitability or large ones with high excitability;

✵ activating Different types of muscle fibers—fast or slow—each relying on distinct energy supply mechanisms;

✵ changing the concentration of ions within the fibers, which activates or inhibits numerous enzyme systems.

Through physical training, neural regulation in skeletal muscles, The Heart, and other organs is refined, contributing to more efficient performance.

Neural and hormonal signals can mutually enhance, suppress, or modify each other's effects. A prime example of their simultaneous and coordinated regulatory influence is the modulation of phosphorylase kinase, an enzyme that stimulates glycogen breakdown (glycogenolysis). As shown in Fig. 105, this enzyme is activated by Ca²⁺ ions entering muscle and liver cells in response to a nerve impulse, as well as by cAMP generated via the action of the hormone adrenaline. When both factors act concurrently, the enzyme achieves peak activity. This dual mechanism ensures fine-tuned regulation of the primary energy-producing pathways during intense muscular exertion to match immediate energy demands.

The mechanisms described above do not encompass the full diversity of metabolic regulation types nor do they capture their entire complexity. Specific organs and tissues play a vital role in integrating metabolism and driving its adaptation during muscular activity.