KIN 340 Chapter 5: Cell Signaling and the Hormonal Responses to Exercise

Phospholipase C Second Messenger Mechanism

-A G protein can also activate a membrane bound enzyme phospholipase C -This causes the phospholipid PIP2 to hydrolyze into two intracellular molecules --> inositol triphosphate (IP3) and diacylglycerol (DAG) -Calcium can bind to calmodulin which alters cellular activity in much the same way as cyclic AMP (previous slide) does -DAG activates protein kinase C which in turn activates proteins in the cell -Cyclic AMP, Ca++, IP3, and DAG all are considered second messengers in the event that a hormone binds to a receptor on the cell

Thyroid Hormones

-Act in a permissive manner to allow other hormones to exert their full effect -No real change in T3 and T4 during exercise

Change in FSH, LH, Progesterone, and Estradiol During Exercise

-Anaerobic performance not affected by menstrual cycle phase -Effect of menstrual cycle phase on time trial endurance performance is mixed (understudied)

Pancreas

-Both exocrine and endocrine functions -Secretes: Insulin Glucagon Somatostatin Digestive enzymes and bicarbonate (exocrine) -Into the small intestine

Magnitude of hormone effect dependent on:

-Concentration of the hormone -Number of receptors on the cell -Affinity of the receptor for the hormone

How is glycogenolysis and plasma epinephrine related to exercise intensity?

-High-intensity exercise results in greater and more rapid glycogen depletion -High-intensity exercise results in greater increases in plasma epinephrine -Plasma epinephrine is a powerful simulator of glycogenolysis

With increased fat mass (obesity)

-Higher leptin levels and lower adiponectin -Leads to type 2 diabetes and low-grade inflammation

Leptin

-Influences appetite through the hypothalamus -Enhances insulin sensitivity and fatty acid oxidation

Insulin Receptor

-Insulin binds to the tyrosine kinase receptor on the alpha receptor on the outside of the cell. -This activates the beta portion which activates signal proteins to signal GLUT4 (for skeletal muscle, adipose tissue, and cardiac tissue) to initiate GLUT4 translocation (the movement of the GLUT4 receptor from the vesicle to the cell membrane. -When GLUT4 receptor is at the level of the cell membrane glucose can enter the cell.

Estrogen and Progesterone

-Released from ovaries -Establish and maintain reproductive function -Levels vary throughout the menstrual cycle

Hypothalamus

-Stimulates release of hormones from anterior pituitary gland by molecules known as: Releasing hormones or factors -Provides hormones for release from posterior pituitary gland

How is GH used?

-Used to treat childhood dwarfism -Also used by athletes and elderly

How do high doses of GH result in more adverse effects than benefits?

-Water retention and edema -Suppression of the GH/IGF axis -No evidence that GH promotes strength gains -Minimal strength gains compared to resistance training alone -Questionable benefits as anti-aging therapy

FFA mobilization

-dependent on hormone sensitive lipase (HSL) -decreases during heavy exercise This occurs in spite of persisting hormonal stimulation for FFA mobilization

Influences on Growth Hormone Release

-exercise -sleep -stress -low plasma glucose

Glucagon

-from alpha cells of the islets of Langerhans -Promotes the mobilization of fatty acids and glucose -Opposite effect of insulin

Insulin

-from beta cells of the islets of Langerhans -Promotes the storage of glucose, amino acids, and fats -Lack of insulin is called diabetes mellitus

Somatostatin

-from delta cells -Controls rate of entry of nutrients into the circulation

What stimulates cells in the kidney to secrete the enzyme renin?

1) Decrease in plasma volume 2) Fall in BP at the kidney 3) Increase in sympathetic nerve activity at the kidney

Control of Cortisol Secretion

1) Exercise/stress 2) Higher brain centers 3) Hypothalamus 4) CRH 5) Anterior Pituitary Gland 6) ACTH 7) Adrenal Cortex 8) Cortisol Cortisol inhibits CRH and ACTH

Mechanism of steroid hormone action

1) Hormone passes through the plasma membrane 2) Inside target cell the hormone binds to a receptor protein in the cytoplasm or nucleus 3) Hormone-receptor complex binds to hormone response element on DNA, regulating gene transcription 4) Protein Synthesis 5) Change in protein synthesis is cellular response

Control of Testosterone Secretion

1) Hypothalamus 2) Gonadotropin-releasing hormone 3) Anterior Pituitary Gland 4) FSH and ICSH (LH) 6)FSH--> Seminiferous tubules--> inhibin and spermatogenesis 6) LH--> Interstitial (Leydig) Cell--> testosterone--> seminiferous tubules and male secondary sex characteristics -Testosterone inhibits gonadotropin releasing hormone and LH -Inhibin inhibits FSH

Control of Estrogen Secretion

1) Hypothalamus 2) Gonadotropin-releasing hormone 3) Anterior Pituitary Gland 4) FSH and LH 5) Ovary 6) Estrogen and progesterone 7) Development of Ovum, Deposition of fat to thighs and buttocks, breast development 8) Ovum--> Inhibin -Estrogen inhibits gonadotropin releasing hormone and LH -Inhibin inhibits FSH

The posterior pituitary releases antidiuretic hormone (ADH). What is the action of ADH? How does exercise impact ADH release?

ADH reduces water loss from the body to maintain plasma volume. During low intensity exercises ADH will not be released. During moderate to high intensity exercises which cause a reduction in plasma volume (remember: you sweat more in moderate/high intensity exercise) ADH will increase with increasing exercise intensity.

Mechanisms of Hormone Action

Activation of genes to alter protein synthesis -Steroid hormones Activating second messengers in the cell via G protein -Cyclic AMP -Ca++ -Inositol triphosphate -Diacylglycerol Altering membrane transport -Insulin via tyrosine kinase

Anterior Pituitary Gland

Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Melanocyte-stimulating hormone (MSH) Thyroid-stimulating hormone (TSH) Growth hormone (GH) Prolactin

What is the role of aldosterone (released from adrenal cortex)? Explain the renin-angiotensin-aldosterone system.

Aldosterone controls the Na+(sodium) water balance. In response to a decrease in plasma volume and sympathetic nerve activity the kidneys will release the enzyme renin. Renin will convert angiotensinogen to angiotensin I. Angiotensin I will be converted to Angiotensin II by ACE (angiotensin-converting enzyme). Angiotensin II will stimulate the release of aldosterone. Aldosterone will increase Na+ reabsorption.

The effect of a hormone on a tissue is determined by which of the following? Rate of secretion of hormone from endocrine gland Rate of metabolism or excretion of hormone Changes in plasma volume All of the above

All of the above

Which of the following activates second messengers via G proteins? Cyclic AMP Calcium Inositol triphosphate All of the above

All of the above

Classes of Hormones

Amino acid derivatives Peptides/protein Steroids

Hormones

Bind to specific protein receptor to exert their effect

Chronic exercise training and sex hormones

Chronic exercise (training) can decrease testosterone levels in males and estrogen levels in females. The latter adaptation has potentially negative consequences related to osteoporosis.

Aldosterone

Control of Na+ reabsorption and K+ secretion -Na+/H2O balance Regulation of blood volume and blood pressure -Part of renin-angiotensin-aldosterone system -All three hormones increase during exercise Stimulated by: -Increased K+ concentration -Decreased plasma volume

Thyroid-stimulating hormone (TSH)

Controls thyroid hormone release from thyroid gland

What does renin do?

Converts angiotensinogen to angiotensin I which in turn converts to angiotensin II by angiotensin-converting enzyme (ACE) in the lungs

Effect of Exercise on Cortisol

Decrease during low-intensity exercise Increase during high-intensity exercise -Above ~60% VO2 max -Changes may be related to repair of exercise-induced tissue damage

Downregulation

Decrease in receptor number in response to high concentration of hormone

Neuroendocrine system

Endocrine system releases hormones into blood to circulate to tissues Nervous system uses neurotransmitters to relay messages from one nerve to another

Dual control of muscle glycogen breakdown

Epinephrine-cyclic AMP -Via β-adrenergic receptors Ca++-calmodulin -Enhanced during exercise due to Ca++ release from sarcoplasmic reticulum -Breakdown of glycogen and the delivery of fuel (glucose) parallels the activation of contraction

Explain how blood glucose homeostasis is maintained during exercise?

Exercise will stimulate an increase in epinephrine, norepinephrine, and glucagon. Exercise will cause insulin to decrease. These will cause adipose tissue to release free fatty acids (FFA) and subsequently cause the liver to release glucose in order to maintain glucose levels. Fat will be the primary source of fuel (sparing glucose/glycogen).

T/F: Glucagon decreases during exercise which helps maintain blood glucose.

False

T/F: Growth hormone increases the use of plasma glucose.

False

The anterior pituitary releases growth hormone. Explain how this occurs. What is the action of GH?

Growth hormone stimulates protein synthesis and growth, increases gluconeogenesis in the liver, and blocks glucose entry into the cell in order to favor FFA mobilization. In response to exercise the hypothalamus will release GHRH (growth hormone releasing hormone). This stimulates the anterior pituitary to release growth hormone. Growth hormone also increases inulin like growth factor (IGFs) which stimulate protein synthesis and growth.

Why does FFA mobilization decrease during heavy exercise?

High levels of lactic acid -Promotes resynthesis of triglycerides Elevated H+ concentration inhibits HSL Inadequate blood flow to adipose tissue Insufficient albumin to transport FFA in plasma

During high intensity exercise we shift from fat to CHO as our main source of fuel. However, the process of blood glucose homeostasis that is stimulated during exercise increases FFA mobilization. How does the shift from fat to CHO occur?

High levels of lactic acid during high intensity exercise promotes the Resynthesis of triglycerides. While triglycerides are being broken down (lipolysis) to make FFA at the same time glycerol phosphate is increasing in response to the lactate which turns FFAs back into triglycerides. This effect counteracts the breakdown of triglycerides and ultimately decreases fat utilization for fuel.

Hormone-Receptor Interactions

Hormones only affect tissues that contain specific hormone receptors

What is the action of cortisol release (from adrenal cortex)?

In response to exercise, bone break, burns, or stress cortisol will be released. Cortisol will increase the mobilization of tissue amino acids, mobilize free fatty acids (FFA), stimulate gluconeogenesis in the liver, and block the entry of glucose into tissue.

Effects of Exercise on Growth Hormone

Increase in plasma GH with increased intensity Greater response in trained runners

Upregulation

Increase in receptor number in response to low concentration of hormone

Adiponectin

Increases insulin sensitivity and fatty acid oxidation

Anabolic Steroids and Performance

Initial studies showed no benefit for developing muscle mass -In contrast to real-world reports -"Subjects" used 10 to 100 times the recommended dosage Also associated with negative side effects -Revert to normal after discontinuation Widespread use has led to testing of competitive athletes Most users are not competitive athletes -Take more than one steroid in megadoses

Effect if exercise on Insulin and Glucagon

Insulin: -Plasma concentration decreases during exercise -Decreased insulin response following training Glucagon: -Plasma concentration increases during exercise -Decreased response following training Insulin and glucagon secretion influenced by catecholamines

Cyclic AMP "Second Messenger" Mechanism

Many hormones, because of their size, cannot easily cross cell membranes These hormones exert their effects by binding to a receptor on the membrane surface and activate a G protein located in the membrane of a cell When a hormone binds to the receptor on the cell membrane it activates a G protein. This activates adenylate cyclase which allows ATP to turn into cyclic AMP. Cyclic AMP then turns inactive protein kinase into active. This signals the hormones cellular response (action of the hormone). This mechanism is used to break down glycogen to glucose and breakdown triglyceride molecules to free fatty acids

Plasma glucose maintained through four processes:

Mobilization of glucose from liver glycogen stores Mobilization of FFA from adipose tissue -Spares blood glucose Gluconeogenesis from amino acids, lactic acid, and glycerol Blocking the entry of glucose into cells -Forces use of FFA as a fuel More important in longer duration work

How do Epinephrine and Norepinephrine maintain blood glucose during exercise?

Muscle glycogen mobilization Increasing liver glucose mobilization Increasing FFA mobilization Interfere with glucose uptake

Posterior Pituitary Gland

Oxytocin Antidiuretic hormone (ADH)

Parathyroid Gland

Parathyroid hormone -PRIMARY hormone in plasma Ca++ regulation -Stimulates Ca++ release from bone -Stimulates reabsorption of Ca++ by kidneys -Converts vitamin D3 into a hormone that increase Ca++ absorption from GI tract -Increases during both intense and prolonged exercise

Plasma GLucose homeostasis controlled by hormones

Permissive or slow-acting -Thyroxine, cortisol, and growth hormone Fast-acting -Epinephrine, norepinephrine, insulin, and glucagon

Evidence for role of Ca++-calmodulin in glycogenolysis

Propranolol (β-receptor blocker) has no effect on muscle glycogen utilization

Plasma concentration determined by?

Rate of secretion of hormone from endocrine gland -Magnitude of input -Stimulatory versus inhibitory input Rate of metabolism or excretion of hormone -Inactivation near the receptor and/or metabolized by the liver and kidneys Quantity of transport proteins -Steroid hormones and thyroxine are transported bound to plasma proteins Changes in plasma volume

Antidiuretic hormone (ADH)

Reduces water loss from the body to maintain plasma volume -Favors reabsorption of water from kidney tubules to capillaries Release stimulated by high plasma osmolarity and low plasma volume -Due to sweat loss without water replacement Increases during exercise >60% VO2 max -To maintain plasma volume

Endocrine glands

Release hormones directly into the blood

Testosterone

Released from testes Anabolic steroid -Promotes tissue (muscle) building -Performance enhancement Androgenic steroid -Promotes masculine characteristics

Adrenal Cortex

Secretes steroid hormones -Derived from cholesterol Mineralcorticoids -Aldosterone -Maintenance of plasma Na+ and K+ Glucocorticoids -Cortisol -Regulation of plasma glucose Sex steroids -Androgens and estrogens -Support prepubescent growth

Adrenal Medulla

Secretes the catecholamines -Epinephrine (E) primary secretion (80%) -Norepinephrine (NE) primarily secreted from the adrenergic neurons of the sympathetic nervous system -Fast-acting hormones -Part of "fight or flight" response -Bind to adrenergic receptors: Alpha Beta -bring about changes in cellular activity (e.g., increased heart rate, mobilization of fatty acids from adipose tissue) via second messengers -Binding to beta can have opposite response than binding to alpha -Effects depend on hormone used and receptor type

Growth Hormone

Slow-acting hormone -Supports the action of cortisol Stimulates release of insulin-like growth factors (IGFs) -IGF-1 in muscle responsible for muscle growth Essential growth of all tissues -Amino acid uptake and protein synthesis -Long bone growth Spares plasma glucose -Opposes insulin action to reduce the use of plasma glucose -Increases gluconeogenesis -Mobilizes fatty acids from adipose tissue

Cortisol

Slow-acting hormone Maintenance of plasma glucose -Promotes protein breakdown for gluconeogenesis in the liver -Stimulates FFA mobilization from adipose tissue -Stimulates glucose synthesis -Blocks uptake of glucose into cells -->Promotes the use of free fatty acids as fuel

Thyroid Gland

Stimulated by TSH -Triiodothyronine (T3) and thyroxine (T4) -Influences resting metabolic rate -Permissive hormones -Permit full effect of other hormones Calcitonin -Involved in the regulation of plasma Ca++ -Blocks Ca++ release from bone, stimulates excretion by kidneys -Not released in response to exercise

Adrenocorticotropic hormone (ACTH)

Stimulates cortisol release from adrenal glands

Luteinizing hormone (LH)

Stimulates production of testosterone and estrogen

How is cortisol stimulated?

Stress, via ACTH -Part of General Adaptation Syndrome (GAS) Exercise

Testes and Ovaries Hormones

Testosterone Estrogen and Progesterone

Blood Hormone Concentration

The effect of a hormone on a tissue is determined by the plasma concentration and the number of active receptors

T/F: Cortisol stimulates free fatty acid mobilization from adipose tissue.

True

Angiotensin II functions

a powerful vasoconstrictor -Individuals with high blood pressure may be prescribed ACE inhibitors -stimulates aldosterone release -Increases Na+ reabsorption

T3

enhances effect of epinephrine to mobilize free fatty acids from adipose tissue

Effects of Exercise on Plasma E and NE

increase during exercise -Also related to increased heart rate and blood pressure during exercise Decreased plasma E and NE following training

adipose tissue secretes what hormones?

leptin and adiponectin