MUSCULOSKELETAL SYSTEM Flashcards
Describe the steps for fracture and bone repair
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.
Types of joints
Fibrous
Cartilaginous
Synovial
Examples of synovial joints
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
Soft tissue structures associated with synovial joints
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
Actions of PTH
Promote release of Ca from bone
Increases renal Ca reabsorption
Increases renal Pi (inorganic phosphate) excretion
Upregulates 1α hydroxylase activity
Actions of calcitrol
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
How is calcitrol formed
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
Actions of FGF-23
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
Myogenesis
- Paracrine factors induce Myogenic commitment (Myf5 and MyoD) (myoblasts)
- Myoblasts proliferate (growth factors)
- Cell cycle exit, Myogenin expression = terminal differentiation
- Structural proteins expressed and myotubes form
- Myotubes align and fuse. Fusion and fibre maturation into muscle fibres
Pax genes involved in muscle regneration
Pax 3
Pax 7
Paired homeodomain transcription factors Pax3 and Pax7
What does Pax 3 do
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
What does Pax 7 do
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
Impact of muscle ageing - SARCOPENIA
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
Biochemical and metabolic changes that occur with muscle ageing
Mitochondrial mutations, reduced oxidative and glycolytic enzyme activity
Reduced endocrine function, reduced physical activity
Type 1 fibres
SLOW MUSCLE Virtually inexhaustible High mitochondria – aerobic Oxidative phosphorylation Extensive blood supply and abundant myoglobin
Type 2 fibres
FAST MUSCLE Fatigues easily Few mitochondria – mainly anaerobic metabolism Glycolytic Poor vascularisation and lack myoglobin
Origins of skeletal muscle
Muscles forms from the somites (paraxial mesoderm) Sclerotome (bone, ribs, cartilage) Myotome (muscles precursors) Dermomyotome (myotome and dorsal dermis) Syndetome (tendons)
Osteoblasts
Bone forming cells from mesenchymal stem cells.
Secrete osteoid, collagen matrix of bone
Promote mineralisation of osteoid
Osteoclasts
Bone reabsorbing cells from haematopoietic stem cells
Secrete acid to dissolve bone mineral and enzymes to digest organic matrix
Osteocytes
Terminally differentiated osteoblasts - encased in bone mineral matrix (lacunae)
Extend multiple dendrites in bone matrix via canaliculi
Thought to coordinate osteoblast and osteoclast activity
Lanocanalicular
System maintains communication with bone surface and blood vessels.
Bone remodelling with RANK ligand
RANK = surface receptor on pre-osteoclasts, stimulate osteoclast differentiation
RANK ligand - bind to RANK and stimulate osteoclast differentiation
Bone remodelling with Wnt signalling pathway
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
Osteoporosis pseudoligma
Inactivation of LRP5, Wnt Co-receptor
Sclerosteosis and van buchem disease
Mutation of SOST gene, inactivating sclerostin protein
Osteopetrosis
Mutation inactivates RANKL protein
Neuromuscular junctions mechanism for contraction
- AP reaches pre-synaptic membrane or motor neuron – ACh is released across the NMJ and bind to nicotinic AChR on post synaptic membrane
- If threshold is met an AP will depolarise the sarcolemma. Depolarisation spreads deep into the cell to the sarcoplasmic reticulum due to T tubules
- Calcium released
- Ca2+ interacts with troponin which displace tropomyosin - myosin binding site exposed - cross bridge formation
- ADP released = power stroke. ATP then binds to myosin to detach from myosin
- Ca2+ transported back to sarcoplasmic reticulum with Ca2+ pump
Single twitch
A single action potential will produce a single twitch lasting 100msec
Summation
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
Tetanus
Rate of action potential so high that muscle does not relax between stimuli = sustained contraction
Duchene muscular dystrophy
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
Amyotrophic lateral sclerosis
Motor neuron disease
Severe disability leading to death from respiratory failure.
Sporadic probability caused by a combination of environmental and genetic factors
NO CURE
Myasthenia Gravis
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
Somatic nervous system
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
Phases of regeneration
- Degeneration/inflammation phase
- Regeneration phase
- Remodelling phase
What happens in degeneration/inflammatory phase
Myofiber rupture and necrosis, formation of hematoma, inflammatory response
What happens in regeneration phase
Phagocytosis of damaged tissue.
Stem cell activation and proliferation
What happens in remodelling phase
Maturation of regenerated myofibers, restoration of blood supply and innervation, recovery of muscle functional capacity and fibrosis and scar tissue formation
Testosterone affect of myogenesis
Promote commitment of mesenchymal pluripotent cells into myogenic lineage and inhibit adipogenesis
Stimulate - satellite cell replication, muscle protein synthesis, fibre hypertrophy
Myosin isoforms
Different chemo mechanical transduction
ATP hydrolysis
Shortening velocity
Myofibrillar protein isoform
Alternative splicing or promoters
Postnatal muscle growth - hypertrophy
After birth increase in muscle mass due to increase in fibre size.
MuSCs proflierate and incorporated - muscle fibres return to quiescence when not needed.
Postnatal muscle growth - hyperplasia
Increase in muscle mass due to increase in cell/fibre number
Proposed mechanism - fibre splitting and stem cell activation
