Skeletal muscle Flashcards
What cell types make up skeletal muscle?
- skeletal myocytes
- endothelial cells of the vascular system which nourishes it
- connective tissue fibroblasts
Describe the hierarchical structure of skeletal muscle (largest to smallest). Where are the nuclei in this structure?
gross anatomical muscle (cm) > fascicles (mm) > skeletal myocytes (aka “fibers”: 10-100 um) > myofibrils (~1 um) > myofilaments (nm)
**hundreds of nuclei at the myocyte periphery
Describe the connective tissue of skeletal muscle
- entire muscle is surrounded by deep fascia aka epimysium
- each fascicle is surrounded by perimysium (continous with CT at myotendon junction)
- each skeletal myocyte within a fascicle is surrounded by endomysium (continuous with the basal lamina/basement membrane)
Describe the striated structure of a myocyte. What is a sarcomere?
Myocytes contain myo_fibrils;_
- light bands (I-bands)
- bisected by a Z-line (contains the protein alpha-actinin)
- dark bands (A-bands)
- H-zone down the middle, bisected by M-line (contains MM-CK)
**sarcomere= area between successive Z-lines (fundamental unit of striated muscle contraction)
Describe myofibril structure
**myofibrils contain myofilaments
- Thick= A bands only
- myosin
- note; A bands are dark because they contain both thick and thin filaments
- Thin= I bands and A bands
- actin, 3 troponins, tropomyosin
- note; I bands are light because they ONLY contain thin filaments
What is a triad?
At the A-I junction, two SR membranes plus one T-tubule membrane
Describe the excitation phase of muscle contraction
**how striated muscle contracts;
- neuron is activated, Ca++ enters
- synaptic vesicles in the nerve terminal fuse with pre-synaptic membrane and empty their contents
- acetylcholine (ACh) enters intercellular space (cleft) -> 2 ACh molecules bind to each acetylcholine receptor (AChR)
- nicotinic AChRs function as Na+ ion channels on the myocyte’s post-synaptic membrane (acetylcholinesterase modulates the extent of synaptic transmission)
- entry of Na+ ions into the myocyte, igniting the action potential -> wave of depolarization runs down the sarcolemma and dives into the T-tubules
- T tubules contain the Ca++ channel protein Cav1.1 (aka DHP receptor)
- Cav1.1 binds a ryanodine (RyR) receptor on the membrane of the SR, causing the SR to release its stored Ca++
What are neuromuscular blockers?
- non-depolarizing agents (curariform drugs), which bind-up ACh ligand
- depolarizing agents such as succinylcholine, which overstimulate the AChR, causing it to become non-reponsive
**have no CNS activity
Describe the contraction phase of muscle contraction
- Ca++ released by the SR binds troponin-C (thin filament protein)
- causes tropomyosin to move, uncovering myosin-binding-sites on actin (thin filament)
- as the thick filament rotates, the myosin head (activated by ATP hydrolysis) binds actin
- myosin head flexes, thin filament move into the A-band
- sarcomere shortens (length of A band unchanged, I band shortens)
How does Striated Muscle Relax?
- Ca++ ion-channel pump (SERCA) in the SR membrane pumps Ca++ back into the SR
- decreased Ca++ -> fresh ATP binds the myosin head -> actin and myosin disssociate -> myocyte relaxes
Describe malignant hyperthermia
- mutation in CACNA1 (gene encoding Cav1.1) or Ryr1 (gene encoding ryanodine receptor) dysregulates Ca++ transport
- leads to sustained contraction -> increased body temp
- fix with dantrolene, a muscle relaxant that blocks Ca++ release from the SR by inhibiting the ryanodine receptor
**contrast rigor mortis= the absence of fresh ATP prevents acto-myosin dissociation, preventing relaxation and resulting in “stiffening“
What is the ratio of thick:thin filaments within a myocyte?
within each myofibril there are six thin filaments surrounding each thick filament
(also parts of the SR membrane system surround each myofibril)
How is energy stored for muscle contraction?
- Skeletal muscle stores energy as ATP, creatine phosphate, glycogen, and fatty acids.
- sprinters use glycogen
- marathoners utilize fatty acids
What are the types of muscle fibers?
- Type I fibers “slow twitch” fibers
- red (enriched in mitochondria and myoglobin)
- for fatty acid oxidation and oxidative metabolism to support relatively continuous contraction
- __Type II fibers “fast twitch fibers”
- white (less myoglobin); glycolytic or mixed oxidative/glycolytic
- modified for rapid, discontinuous contraction
- sub-classified as Type IIA, IIB and IIC, based on biochemical composition
From what type of cell does skeletal muscle regenerate? What signals regulate the process?
- via Resident Adult Stem Cells (mononuclear, residing between the sarcolemma and the basal lamina of the skeletal myocyte; their niche)
- also called satellite cells/skeletal myoblasts
- normally arrested in Go phase (thanks to myostatin) of the cell-cycle (re-enter cycle when basal lamina is damaged and releases growth factors)
Describe the steps of skeletal muscle regeneration
- Resident Adult Stem Cells are stimulated by growth factors to leave the Go phase and begin division/expansion
- after expansion, the cells irreversibly withdraw from the cell-cycle and fuse together, forming multinuclear muscle cells termed myotubes
- myotubes undergo robust muscle differentiation and can regenerate entire muscles
Describe the timeline of skeletal muscle regeneration
- Day 0: injury or insult to basal lamina
- Days 1-7: Satellite cells proliferate; during this time, the stem cells compete with invading fibroblasts.
- Day 7: Myotubes form. Myotubes are new, embryonic-like skeletal muscle cells.
- Day 14: Many myotubes are present.
- the myotubes fuse with each other, and to the original myocyte.
- forms “branching” muscle cells with central nuclei.
- innervation begins.
- Day 21: Functional skeletal muscle cell.
**Note that by age 60, because we have diminished numbers of stem cells (including satellite cells), regeneration is diminished
How were satellite cells used in an attempt to treat Cardiac Insufficiency?
- myo-satellite cells were harvested from thigh and leg muscles of ~300 patients with cardiac-insufficiency
- followed by autologous transplantation into the heart (in an attempt to enhance ejection fraction)
- results indicated modest improvement, but instances of arrhythmia caused this treatment to be discontinued
How were satellite cells used in an attempt to treat Duchenne Muscular Dystrophy (DMD)?
- DMD= from mutations in the gene encoding dystrophin, a sub-sarcolemmal protein that helps stabilize the myocyte cytoskeleton
**treat with prednisone or gentamicin which enables translational read-through of the stop codons… some possible other treatments=
- cellular therapy using myo-satellite or bone marrow-derived adult stem cells
- gene therapy by introducing normal dystrophin genes into skeletal myocytes via adenovectora
- use of orally administered drugs, such as PTC124, whose proprietary design circumvents the stop signals in the mutated gene
- inhibition of myostatin
