MUSCULOSKELETAL SYSTEM

Question 1

Describe the steps for fracture and bone repair

Answer 1

Treated by immobilisation and realignment
Haematome - blood clot forms at the fracture site.
New vessels grow - soft callus formed.
Replaced by a bony callus.
Bony callus is remodelled to form a permanent patch.

Question 2

Types of joints

Answer 2

Fibrous
Cartilaginous
Synovial

Question 3

Examples of synovial joints

Answer 3

Hinge – elbow, fingers
Ball and socket – shoulder, hip
Pivot – rotation – neck, radio humeral
Saddle – thumb – carpometacarpal joint
Gliding – flat surfaces, sliding movement – carpals
Condylar – oval shaped articular surfaces – mcp joints, movement in 2 planes

Question 4

Soft tissue structures associated with synovial joints

Answer 4

Capsule – fibrous layer around the joint, lined with synovial membrane
Bursa – flattened fibrous sac, lined with synovial membrane for lubrication
Synovial sheath – elongated bursa that wraps around a tendon

Question 5

Actions of PTH

Answer 5

Promote release of Ca from bone
Increases renal Ca reabsorption
Increases renal Pi (inorganic phosphate) excretion
Upregulates 1α hydroxylase activity

Question 6

Actions of calcitrol

Answer 6

Increased by – PTH, Low phosphate
Increase absorption of Ca and Pi from GI tract
Inhibit PTH secretion (transcription)
Complex effects on bone, generally in synergy with PTH

Question 7

How is calcitrol formed

Answer 7

Vitamin D produced in the skin and then converted into calcitrol.
25 hydroxylation in liver to form 25OH D3, major circulating metabolite
1α hydroxylation of 25 OH D3 in kidney produces 1,25(OH)2 D3, or calcitriol, the active hormone

Question 8

Actions of FGF-23

Answer 8

Expressed and secreted by osteocytes
Increases renal Pi excretion (by reducing Na-pi reabsorption from proximal tubule)
Increased by calcitriol and Pi
Inhibits calcitriol synthesis

Question 9

Myogenesis

Answer 9

1. Paracrine factors induce Myogenic commitment (Myf5 and MyoD) (myoblasts)
2. Myoblasts proliferate (growth factors)
3. Cell cycle exit, Myogenin expression = terminal differentiation
4. Structural proteins expressed and myotubes form
5. Myotubes align and fuse. Fusion and fibre maturation into muscle fibres

Question 10

Pax genes involved in muscle regneration

Answer 10

Pax 3
Pax 7
Paired homeodomain transcription factors Pax3 and Pax7

Question 11

What does Pax 3 do

Answer 11

Pax 3 establish MuSCs identity during embryonic development
Expressed in the presomitic mesoderm, required for survival of the ventro-lateral dermomyotome, which gives rise to the hypaxial and limb musculature

Question 12

What does Pax 7 do

Answer 12

Pax 7 establishes MuSCs during late foetal and perinatal growth
Pax7 null mice are deficient in the number of MuSCs and fail to regenerate muscle after injury in adult mice

Question 13

Impact of muscle ageing - SARCOPENIA

Answer 13

3-8% decrease per decrease after the age of 30, higher after 60
Impact on the elderly – falls, injury, disability
Loss of muscle mass associated with gain in fat mass
Associated with decreased satellite cells number and recruitment

Question 14

Biochemical and metabolic changes that occur with muscle ageing

Answer 14

Mitochondrial mutations, reduced oxidative and glycolytic enzyme activity
Reduced endocrine function, reduced physical activity

Question 15

Type 1 fibres

Answer 15

SLOW MUSCLE
Virtually inexhaustible 
High mitochondria – aerobic
Oxidative phosphorylation
Extensive blood supply and abundant myoglobin

Question 16

Type 2 fibres

Answer 16

FAST MUSCLE
Fatigues easily 
Few mitochondria – mainly anaerobic metabolism 
Glycolytic 
Poor vascularisation and lack myoglobin

Question 17

Origins of skeletal muscle

Answer 17

Muscles forms from the somites (paraxial mesoderm)
Sclerotome (bone, ribs, cartilage)
Myotome (muscles precursors)
Dermomyotome (myotome and dorsal dermis)
Syndetome (tendons)

Question 18

Osteoblasts

Answer 18

Bone forming cells from mesenchymal stem cells.
Secrete osteoid, collagen matrix of bone
Promote mineralisation of osteoid

Question 19

Osteoclasts

Answer 19

Bone reabsorbing cells from haematopoietic stem cells

Secrete acid to dissolve bone mineral and enzymes to digest organic matrix

Question 20

Osteocytes

Answer 20

Terminally differentiated osteoblasts - encased in bone mineral matrix (lacunae)
Extend multiple dendrites in bone matrix via canaliculi
Thought to coordinate osteoblast and osteoclast activity

Question 21

Lanocanalicular

Answer 21

System maintains communication with bone surface and blood vessels.

Question 22

Bone remodelling with RANK ligand

Answer 22

RANK = surface receptor on pre-osteoclasts, stimulate osteoclast differentiation
RANK ligand - bind to RANK and stimulate osteoclast differentiation

Question 23

Bone remodelling with Wnt signalling pathway

Answer 23

Frizzled = Wnt receptor - requires co receptor LRP5 to work
SOST and LRP5 prevent Wnt activation - promote bone formation (osteoblast differentiation) so this negative regulation acts as a brake

Question 24

Osteoporosis pseudoligma

Answer 24

Inactivation of LRP5, Wnt Co-receptor

Question 25

Sclerosteosis and van buchem disease

Answer 25

Mutation of SOST gene, inactivating sclerostin protein

Question 26

Osteopetrosis

Answer 26

Mutation inactivates RANKL protein

Question 27

Neuromuscular junctions mechanism for contraction

Answer 27

1. AP reaches pre-synaptic membrane or motor neuron – ACh is released across the NMJ and bind to nicotinic AChR on post synaptic membrane 2. If threshold is met an AP will depolarise the sarcolemma. Depolarisation spreads deep into the cell to the sarcoplasmic reticulum due to T tubules 3. Calcium released 4. Ca2+ interacts with troponin which displace tropomyosin - myosin binding site exposed - cross bridge formation 5. ADP released = power stroke. ATP then binds to myosin to detach from myosin 6. Ca2+ transported back to sarcoplasmic reticulum with Ca2+ pump

Question 28

Single twitch

Answer 28

A single action potential will produce a single twitch lasting 100msec

Question 29

Summation

Answer 29

If 2nd AP arrives before muscle has relaxed get greater tension During summation high freq. AP maintain a high conc. of Ca2+ in cytosol of muscle fibre – prolonging cross bridge cycling and causing greater stretching of elastic structures

Question 30

Tetanus

Answer 30

Rate of action potential so high that muscle does not relax between stimuli = sustained contraction

Question 31

Duchene muscular dystrophy

Answer 31

Common severe form of childhood muscular dystrophy MUTATED GENE = DYSTROPHIN Connects actin filament to the sarcolemma - required for stability Lack of dystrophin leads to dysfunction of sarcolemma stretch - ion pores open and increased intracellular Ca2+ Degradation of structual proteins, CK - CK needed for ATP

Question 32

Amyotrophic lateral sclerosis

Answer 32

Motor neuron disease Severe disability leading to death from respiratory failure. Sporadic probability caused by a combination of environmental and genetic factors NO CURE

Question 33

Myasthenia Gravis

Answer 33

Chronic autoimmune NMD results in skeletal muscle weakness and fatigue Body makes antibodies against AChRs at NMJs Blocks AChRs. Increase AChR degradation and causes impaired signal transduction Treatment - Acetyl cholinesterase inhibtors

Question 34

Somatic nervous system

Answer 34

Part of the peripheral nervous system Provide voluntary control over skeletal muscle Upper motor neurons in brain connect with lower MN in spinal cord - signal to muscle

Question 35

Phases of regeneration

Answer 35

1. Degeneration/inflammation phase 2. Regeneration phase 3. Remodelling phase

Question 36

What happens in degeneration/inflammatory phase

Answer 36

Myofiber rupture and necrosis, formation of hematoma, inflammatory response

Question 37

What happens in regeneration phase

Answer 37

Phagocytosis of damaged tissue. | Stem cell activation and proliferation

Question 38

What happens in remodelling phase

Answer 38

Maturation of regenerated myofibers, restoration of blood supply and innervation, recovery of muscle functional capacity and fibrosis and scar tissue formation

Question 39

Testosterone affect of myogenesis

Answer 39

Promote commitment of mesenchymal pluripotent cells into myogenic lineage and inhibit adipogenesis Stimulate - satellite cell replication, muscle protein synthesis, fibre hypertrophy

Question 40

Myosin isoforms

Answer 40

Different chemo mechanical transduction ATP hydrolysis Shortening velocity

Question 41

Myofibrillar protein isoform

Answer 41

Alternative splicing or promoters

Question 42

Postnatal muscle growth - hypertrophy

Answer 42

After birth increase in muscle mass due to increase in fibre size. MuSCs proflierate and incorporated - muscle fibres return to quiescence when not needed.

Question 43

Postnatal muscle growth - hyperplasia

Answer 43

Increase in muscle mass due to increase in cell/fibre number Proposed mechanism - fibre splitting and stem cell activation