BIOCHEMISTRY OF

BONE AND MUSCLE

RONDANG SOEGIANTO
2012

BONE
- Skeleton contains 99% body Ca2+
- Bone marrow = manufacturer of
red blood cells
- Storage for Ca2+ and PO43-

Hormone involved
Parathyroid H (PTH) = a peptide
Secreted by parath glands
Overall effects:
- Increase plasma Ca conc
- Lowers PO4
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Extracellular Matrix
Principal part of bone:
- Hydroxyapatite crystals
= Precipitated Ca4(PO4)2
crystallyze around collagen
fibers in matrix

PTH mobilizes Ca from store

(=bone) to raise
plasma Ca when it starts to <<
Bone Remodeling
- Bone deposition
- Bone resorption
Continuous turnover of bone
resorption
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Three types of bone cells

- Osteoblasts secrete extracellr
organic matter
Precipptd by Ca-Phosphate
crystals
- Osteocytes
Retired osteoblasts
Surrounded by bony deposits
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- Osteoclasts
Resorb bone by releasing acids
Ca-Phosph crystals dissolved
Enzymes break down organic
matter
# Bone mass remains fairly
constant
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Balance Between Bone Resorption

and Deposit
Osteoblasts produce
- Osteoprotegerin (OPG)
- Osteoprotegerin Ligand (OPGL)
OPGL binds to surface receptor on
osteoclast activity >>
bone resorption >> Bone Mass
<<
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OPG secreted by osteoblasts into

matrix bind with OPGL
inhibits osteoclast activity
Bone Mass>>
Balance between OPGL and OPG
determines Bone Density
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Female sex H estrogen

stimulatesactivity of OPG gene in
osteoblast.
Helps preserve bone mass.
Osteoporosis = Decrease in bone
density
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Type I: Prevails among

postmenopausal women
Decreased estrogen
- osteoclast activity >>
- osteoblast activity <<
Cause brone fracture, spinal
deformity
Type II: Males and Females in aging
<< ability to absorb Ca2+
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Effects of PTH on Bone

Bone = Ca bank consists of
- Labile pool = Bone fluid
- Stable pool = Mineralized bone
1 PTH induces fast Ca efflux into
plasma from labile pool
2 Promotes slow transfer into
plasma of Ca and PO4 from
stable pool

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# PTH favors bone resorption

over bone deposition
Promotes Ca transfer from
bone fluid into plasma

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Mechanism of Ca Mobilization
PTH activates membr-bound Capumps in plasma membra of
ostecytes and osteoblasts
Promotes Ca transp without PO4
from bone fluid into these cells.
From here, Ca transf into plasma
within central canal
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Thus: PTH stimulates transf of Ca

from bone fluid osteocyteosteobl bone membr into plasma
PTH immediate effect:
Promotes transfer of Ca from
bone fluid into plasma
This is fast exchange between
bone and plasma
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Next: Ca from partially

mineralized bone along bone
surface goes into bone fluid.
# Bone mass not <<

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Slow exchange:
Occurs between bone and Extra
Cellular Fluid (ECF)
- Dissolution of bone during
chronic hypocalcemia
(Dietary Ca deficiency)
- Osteoclasts digest bone and
increase more osteocl formation
- Osteoblasts activity inhibited
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Fast exchange > important than

slow exch for maintaining Ca
conc
Ca content of bone > 1000 times
plasma conc
Effect of PTH on bone resorption
does not disturb
skeletonintegrity.

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On the other hand, Ca release very

important to maintain free plasma
Ca2+ level
Hazardous if excess PTH secretion
lasts for months, years may
cause cavities throughout
skeleton
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Dissolution of Ca-Phosph by PTH

to raise plasma Ca will also >>
PO4 conc of plasma.
Kidney excretes excess PO4 and
reabsorbs Ca
Increase of plasma PO4 can
recrystalize Ca2+ not effective
to maintain plasma Ca
# PTH secretion = response to
drop of plasma CA

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Calcitonin
H produced by C cells of thyroid
gland 2 effects on bone, both <<
plasma Ca
1 Short term: << Ca movement
from bone fluid plasma
2 Long term: inhibits osteoclast
activity
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When bone resorption <<

Plasma Phosph and Ca <<
Effect of calcitonin entirely onbone
No effect on kidney and intestine
Primary regulator of PTH and
calcitonin release is
free plasma Ca2+ conc.
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Calcitonin protects against

hypocalcemia, a rare condition
Plays a role to protect skeletal
integrity when large amt Ca
In demand: - pregnancy
- breastfeeding
Also: Favors Ca storage after
meals
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MUSCLE
Muscle transduces chemical
energy mechanical E
E sources: Glucose (Glycogen)
Fatty acids
Ketone bodies
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Glucose
Transporter = Glut 4
Activated by hexokinase in
muscle Gluk 6-P
Glycolysis: Anaerobic Lactate
Aerobic Pyruvate
TCA cycle
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Fatty Acid
Beta oxidation in mitochondria
FA activated by linkage as
thioester to CoASH
Ketone Bodies Acetyl CoA
TCA

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Sources of Glucose
1 Glucose-Alanine Cycle
Alanine (also Glutamine) major
AA release from musle thru
metabolic process via pyruvate.
2 Cori Cycle
Lactate released from muscle
glucose in liver
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3 Glycogenolysis
Activation by phosphorylase,
Ca2+ and epinehrine
Regulation by cyclic AMP:
Glycogen synthase and Glycogen
phosphorylase reciprocally
regulated
Muscle glycogenolysis does not
release glucose into plasma
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Muscle Activity in Exercise

Energy provided by anaerobic and
aerobic metab
Lactate from anaer metab increase
acidity muscle fatigue due to
increased H+ conc, which causes
- Less release of Ca2+ from
sarcopl retic
- Less activity of actomyosin
ATPase
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Sustained Contraction of Muscle

(e.g. to maintain posture) O2
attached to heme of myoglobin
(red muscle)
White muscle: little or no
myoglobin present
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Vasodilators Enhance Muscle

Activity
Vasodilators such as
acetylcholine and NO interact
with walls of small blood vessels
via receptors.

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Increase flow of blood glucose to

enter muscle cells for energy
metabolism
Switch from anaerobic to aerobic
metabolism at
start of exercise.
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Creatine Phosphate Shuttle

Use of skeletal muscle fuel
depends on level of activity.
Skeletal muscle has large mass.
With low metab rate at rest, large
proportion of
bodys energy still used
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Metab range from resting stage to

max activity
200 1000 times
Immediate available substrates
are from muscle itself
- Creatine phosphate (CP)
- Glycogen
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Sprinting
Anaerobic glycolysis
1. ATP ADP + Pi + E
2. Increase of ADP triggers use
of CP to maintain ATP conc
3. Next: Glycogen Lactate

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Thousand Meter Run

1 Anaerobic glycolysis
2 Oxidative metab using
glycogen and glucose
Increase of glycogen metab
controlled by Adrenalin
secretion Protein kinase A,
which is cAMP dependent.
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Marathon
Energy from fat metabolism,
hence low velocity since fat
metab is slower
For several hours run will be
used:TAG and glycogen for 98%
energy need Protein 2%
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Evidence for switch to fat metab

during marathon
- Resp Quotient (RQ = CO2/O2)
declining
- Blood glucose << during
marathon
- Almost 90% glycogen used
- Insulin levels decrease gradually
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Chemical Messenger in Exercise

Epinephrine is released during exercise
stimulation and induce
- Glycogenolysis
- Gluconeogenesis
After 40-240 min. exercise fatty acids are
released from TAG in adipose tissue
Insulin decreased
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Steroid Hormone: Cortisol

Synthesized and released from
adrenal cortex
Stimulated by ACTH
Induce transcription of gluconeogenic
enzymesin prolonged exercise and
other activities.
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Production of blood glucose by the liver

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NEUROTRANSMITTERS (NT)
- Secreted from neurons in response to
stimulus
- Stimulus = Action Potential
Voltage difference across plasma
membrane by changes in Na+ and K+
gradients along a nerve
(see Sherwood p. 115)
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Acetylcholine (ACh)
ACh = NT at neuromuscular junction
Transmits signal from motor nerve
muscle fiber consequently elicits
contraction of fiber
Before release: ACh sequestered in
vesicles
Membrane also has voltage-gated
Ca2+ channels.
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Channels open when action potential

reach them influx of Ca2+
Ca2+ triggers fusion of vesicles with
plasma membrane ACh released
into synaptic cleft.

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NICOTINIC ACETYLCHOLINE RECEPTOR

ACh diffuses synaptic cleft
binds to plasma membrane receptor in
muscle cell = nACh receptor

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After ACh binds to receptor

Conformational change that opens
channels
Na+ diffuses in, K+ diffuses out
Next: Change in ion conc. activates
sequence
of events that at the end will cause
fiber contraction.
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Termination of Message by ACh

As soon as ACh secretion stops, message
is terminated by ACh esterase.
This will decrease ACh concentration
Also: ACh diffuses away from synapses

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MYASTHENIA GRAVIS (MG)

- Autoimmune disease
- Antibodies produced against ACh receptors
in skeletal muscle
- Antibodies bind to receptors
formation of receptor-antibody complex
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- Complex is endocytosed
Degraded in lysosomes
Consequence:
- Fewer functional receptors for ACh
activation
- Less stimulation for repeated muscle
contraction
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Complains and symptoms of MG patient:

- Muscle fatigue in lower extremities
upon walking, but
leg strength returns to normal after
5-10 minutes rest
- Decreased ability to form words when
making a conversation (phone calls)
- Drooping upper eyelids
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MG INHIBITOR TEST
Edrophonium chloride = Inhibitor of
ACh esterase, enzyme that hydrolyzes
Acetylcholine.
Intravenous administration
Inhibition of ACh esterase
Accumulation of ACh that is released
from nerve terminal
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Result:
Higher concentration of ACh
Higher probability of being occupied
and activated.
Improves muscle weakness in patients
with Myasthenia Gravis
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References:
- Human Physiology, L. Sherwood 2004
- Concepts in Biochemistry, Boyer, R. 1999
- Master Medicine, Medical Biochemistry 2005
- Marks Basic Medical Biochemistry 2009

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