Week 6

what happens if you remove hypophysectomy (anterior pituitary) in an animal that hasn't fully grown yet?

animal will stop growing and stay small (no more bone elongation, narrower GPs bc cartilage is not growing due to no proliferative and hypertrophic zones)

recap! what CT membrane encapsulates the whole anatomic organ of bone? how about muscle?

bone: periosteum muscle: epimysium

muscles have what kind of organization?

bundle within bundle like Russian Doll Mamushka (just like collagen, muscle fibers get their strength from small units arranged together) -muscle fibers/cells individually surrounded by epimysium are organized into fascicules surrounded by perimysium which are organized into anatomical muscle surrounded by epimysium -these 3 CT coalesce into tendon that provides strength and F transmission of each individual myofibril within each muscle fiber/cell

the hypophysis produces lots of other hormones like PRL, FSH, LH, etc. how do we know it's GH that causes reduced growth when removed?

by observing GH replacement! if you add only GH to hypophysectomized animal, GP will widen again and cartilage will proliferate and hypertrophy and resume near-normal bone growth

finally, the hormone that counteracts the actions of PTH and Vit D/calcitriol is what?

calcitonin -produced in C cells of thyroid gland -counteracts PTH actions (so DEC blood Ca) -dec bone resorption (direct effect on osteoclasts) -inhibits Ca absorption by intestines -inhibits reabsorption of Ca by kidneys, allowing urinary Ca secretion

what do skeletal muscle fibers/cells contain?

contain standard organelles but specialized to muscle fxn -100s of nuclei along fiber, just beneath sarcolemma (contraction apparatus occupies most of mass inside fiber, so nuclei are pushed to periphery to allow myofibrils to be neatly organized and not be interrupted) -mitochondria b/w contractile elements bc that's where ATP will be used; concentration varies with fiber type -ribosomes dispersed in sarcoplasm (very few on SR bc few secreted proteins) -SR is like ER, but also regulates Ca2+; AP causes release of Ca from SR, stimulating contraction -transverse tubules (triads) TT, continuous with sarcolemma (TT's run inward from surface of fiber and are sandwiched b/w 2 SR's to form triads. SR's do not open onto surface of muscle fiber) -contractile machinery = myofibril, sarcomeres -motor end-plate: neuromuscular junction , connection of nerve cell with muscle cell (where muscle joins nerve that will provide conscious stimuli, so it must be connected to CNS through motor end-plate which is junction of neural terminal and muscle cell)

myofibrils are organized in order to do their function which consists of what 2 things?

contract to allow muscle movement, but also translate that F of contraction toward collagen fiber running through endomysium that coalesces with perimysium and epimysium to become tendon anchored to bone, and that is what results in effective movement!

GP never closes in some animals like what?

crocodiles and alligators

at same time that PTH inc blood levels of Ca, PTH also does what?

dec phosphate (P) in blood via renal excretion at kidneys, thus preventing harmful CaPO4 precipitates in tissue. bc when you inc Ca levels, that may combine with phosphate to produce hydroxyapatite crystals that can lead to calcification of soft tissue so no bueno

when trying to grow an animal for meat/show, be careful not to use what?

don't use too many GC's to treat inflammatory diseases and also make sure to dec their stress

what is the way that GH acts on tissue?

dual effector theory: GH acts to cause differentation of precursor cells, then also stimulates secretion of IGF-1, which has mitogenic effect (start mitosis) on the differentiated cells to proliferate -GH interacts directly with GHR on cell membranes to prime chondrocytes to respond to IGF-1 -stimulates local production of IGF-1 by chondrocytes in the proliferative zone -locally-produced (paracrine) IGF-1 stimulates direct proliferation and hypertrophy of chondrocytes that causes GP growth

how is DMD different b/w men and women?

dystrophin gene is on X chrom, so women have 2 copies while men only have 1. if one gene gets mutated, women have another so they are fine (that's why DMD is p common, it's found in 1 out of 3000 bc it's maintained in population by hiding in heterozygous females) but if men inherit the mutant allele they will be affected

some people worry about what objects, that they will interfere with the electrical current that communicates periosteum to GP?

electric blankets and high-voltage power lines

troll clicker: this drawing represents a cross-section of muscle fibril, showing organization of thick and thin filaments. T/F?

false! bc it's not a drawing... it's an actual electron micrograph pic (omg) anyways, p amazing that our bodies can organize this intricate arrangement! at smallest level, we have sarcomere (minimal part of contraction) with myosin and actin filaments which make up myofibrils which are surrounded by triads of SR containing Ca and TT to allow for quick spread of AP signal. and the whole thing is surrounded by membrane to make one fiber, then many fibers in a bundle called fascicule, and many of those bundles together surrounded by epimysium to make the actual muscle, and all of the CT coalesces into a tendon!

sarco prefix/meaning def?

flesh, muscle (for bone, we only had a single term "osteo." for muscle, we have two terms "myo" and "sarco") -sarcoplasm: cytoplasm of muscle fiber -sarcoplasmic reticulum (SR): ER of muscle fiber -sarcomere: unit of muscle contraction -sarcolemma: cell membrane (plasma membrane + basement membrane + reticular fibers)

muscle attachments are what?

fleshy or tendons (some muscles don't end up as tendon but become fleshy attachment like scapula muscle is spread out and attached to whole bone. on other hand, tendon goes to humerus to provide movement) -origin: least movable attachment (usually proximal) (end of muscle that is relatively stationary during contraction) -insertion: most movable attachment (usually distal) (end of muscle that moves toward origin during contraction) muscles attach to bone. muscles are a network of CT with endomysium, perimysium, and epimysium all coalescing toward the end of muscle and end up at tendon which attaches to periosteum of bone.

what was the first major regulator identified?

growth hormone (1920s-30s)

main regulator of bone growth is what?

growth hormone (GH)

what happens if you castrate male cattle?

he grows bigger than whole male bc castrated animal doesn't have high T production at puberty from testicles, so GP will continue to grow

does muscle consume a lot of E?

heck yes. muscle is 30-40% of body mass, and tissue is alive so it req lot of E, which is important for understanding efficient animal production

what is another way to have inc growth due to dec in tension?

if one GP is damaged/closes prematurely, other GP may compensate by more rapid proliferation (bc growth via only one GP puts less tension on the periosteum so the GP will grow faster)

it is mostly E that affects growth. how?

interacts both at level of cartilage by stimulating cartilage growth but also at pituitary by stimulating GH secretion -affects GH/IGF-1 axis: at puberty, E inc GH pulsatility (rate and amount per pulse) and thus inc IGF-1 -too much/too little E affects GP function (precocious puberty, neutering, therapeutics)

from animal production meat quality POV, what muscle fiber type is desirable?

it's believed that white fiber (FG) makes meat more tender bc they're bigger. compare red (chicken leg) and white meat (chicken breast). white meat is softer bc fibers are bigger, and bigger fiber means less CT around them so they break more easily. also, they tend to be sweeter bc store more glycogen. conversely, red fibers make meat tougher but more flavorful bc red fibers are more commonly surrounded by adipose bc FA's can be used for metabolism via ox phos

muscle cell we call it muscle fiber why?

it's not really cell bc it has many nuclei, so it's more like multiple muscle cells and it has elongated form so we call it a fiber

how is E related to maintenance of bone health?

lack of E during menopause can cause osteoporosis = excess bone loss (dec E levels means no more inhibition of osteoclast activity aka bone resorption) remember to be careful about E supplementation tho! mammary gland cancer yo

the diff CT's surrounding muscle fibers and fascicules and the whole muscle organ are made up of collagen, which recall takes time to mature/strenghten. so collagen, the main composition of endomysium, is one main factor that affects what?

meat quality! tenderness of meat depends on how mature the endomysium is. in young animals, collagen hasn't matured yet so more tender. and perimysium is main location for intramuscular fat deposition aka marbling in meat, which is provides flavor and also inc tenderness bc fat is less dense than muscle

myo prefix meaning/def?

muscle

describe how muscle fibers are organized with SR and TT in order for all of the contractile elements to contract at once (cells are tiny so they must work in tandem. wouldn't work if only one sarcomere contracted)

muscle fibers are long, and SR are organized periodically along the dark and clear bands of muscle. they're associated with TT, which are invaginations of membrane. sarcolemma covers whole muscle fiber, but there are some points where the membrane invaginates deep into cell called TT's (so they are continuations of the sarcolemma). and the TT's form triads with 2 SR's, 1 on each side. an electrical AP will come through membrane for rapid signaling, going deep inside cell via TT's to activate SR to release Ca all together and cause nearby myofibrils to contract in coordination

muscle produces lot of protein! recall fibroblasts produce lots of protein, but it was mostly collagen and proteoglycans for ECM which got exported via ribosomes on ER (rough ER). what about muscle fibers/cells? tl;dr what's diff b/w ribosomes/ER of muscle fibers vs fibroblasts?

muscle fibers produce contractile proteins needed WITHIN cell so they don't export their proteins. so their ribosomes are free-floating in sarcoplasm, not associated with SR

lastly, myofibers also contain cytosolic proteins which are what?

muscle is higher E user! effective way to get energy/ATP is through ox phos of glucose, which req O2. -myoglobin: O2-binding protein (O2 is transported by RBC's which contain Hb which bind to O2 and give O2 to muscle cell which contains similar protein Mb to hold it until needed. bc you don't want loose O2 bc very reactive!!! diff muscle cells contain diff amounts of Mb. ones that rely more on ox phos like red cells contain more Mb. others are more glycolysis dependent and have less Mb) -phosphofructokinase: 1st rate-limiting enzyme in glycolysis, controls 1st step of glycolysis so you need this if you want to undergo glycolytic ATP production -fructose biphosphatase: allows muscle to be a bit more efficient during glycolysis by forming futile cycle with PFK -phosphorylase: mediates glycogen breakdown (glucose is needed to contraction, but cells can't store glucose bc it attracts water and too much glucose would cause bloat/explode, so glucose is stored as glycogen) -lactate dehydrogenase: converts pyruvate to lactate in glycolysis -adenylate kinase: activates glycolysis by increasing AMP when ATP is depleted (helps maintain ATP levels) -succinate dehydrogenase: enzyme in mitochondria for oxidative phosphorylation for TCA cycle to get more ATP from 1 glucose molecule than you'd normally get with just glycolysis alone

why are skeletal muscle cells multinucleated?

muscle is mostly protein, and one nucleus can only make so much protein. very long muscle cell need lots of nucleus to support cell size

what is the contractile machinery inside muscle cell?

myofibrils! they go along whole length of cell and are made up of contractile proteins. they make up the bulk of muscle cell mass. they are fiber of contractile elements bound together to provide strength. myofibrils are divided into sarcomeres, which are units of contraction

if muscle is going to use ox phos pathway, a requirement is O2, which comes with blood. but remember myofiber is large, so for O2 to diffuse in and out of muscle would be inefficient. So muscle has what?

myoglobin Mb, their own O2 molecule to help transport and hold onto O2 (recall Hb is RBC's way of transporting O2)

is there a general rule for GP closure?

no general rule/pattern (proximal vs distal) and no single event that causes closure (GP closures occur over several years). but there are some factors that can affect GP closure

abnormalities of GH function?

obv, too much GH = too much growth of both muscle and bone since GH also stimulates muscle growth! GIANTS: -excess GH prior to GP closure aka GP still active -wider proliferative zone -delayed GP closure -grow bigger/taller (ex. Messi was tiny as a kid due to insufficient secretion of GH so he received therapy) ACROMEGALY: -excess GH after GP closure -growth by apposition only (at this point bone can no longer elongate, it can only grow wider) -affects mainly cranium, digits, feet (flat bones which grow via apposition) -leads to bigger and bony face, widens jaw -very common for people with gigantism to also have acromegaly DWARFISM: -several types, including: -hypopituitary aka small pituitary gland (low GH) -Laron (high GH but low IGF-1. not good bc remember GH acts indirectly through IGF-1) -pygmies (normal GH and IGF-1, but tissues unresponsive) -hypothyroid

(just read) how muscle contraction/relaxation requires ATP: -ATP binding to cross-bridge necessary for detachment of myosin from actin -hydrolysis of ATP activates (cocks) myosin cross-bridge -E from hydrolysis of ATP drives Ca pump for Ca2+ transport into SR

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fun fact! Vit D can also aid in tumor suppression

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note: female E inc GH at younger age than male T does. that's why females start growing bigger earlier

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note: some old people use GH therapy bc GH production diminishes w/age, and that leads to dec muscle tonacity and bone health. but be careful not to supplement too much bc it leads to acromegaly. just ask Sylvestor Stallone!

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note: sometimes kids have pain during growth spurt bc leg bone is growing fast and that causes stretching tension on periosteum

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note: we didn't go over this slide, but IGF-1 inc osteoblast DNA exp and collagen and dec osteoclast resorption (basically bone growth)

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note: we'll focus on striated and skeletal muscle bc that's main part of body we're interested in for meat production and animal performance in work/sport. but before we do that, a few words on smooth muscle

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now, MOVING ON TO MUSCLE! main fxn is movement/locomotion. very important for breathing, digestion, vision, blood circulation.

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all muscle originates on one side of ______ and terminate on other side of ______

originate on one side of joint and terminate on other side of the articulation (so they connect 2 diff bones). in fact, many muscles are named based on where they start and end! there wouldn't be any point in having 1 muscle connect w/n a bone since there's no movement possible there

what hormone regulates levels of Ca in blood (aka calcemia)?

parathyroid hormone (PTH) -main role: inc Ca levels in blood -released by parathyroid gland in response to low plasma Ca and undergoes further processing in liver -raises plasma Ca by stimulation of: 1) bone resorption by osteoclasts 2) kidney (renal tubule) reabsorption of Ca 3) absorption of Ca from GI tract (and bone resorption) by activating Vit D aka 1-25-(OH)2D3 in kidney

the relationship b/w periosteum and putting a break on bone growth can be exploited to correct some growth defects how (removal of tension)?

periosteum stripping: cut into periosteum and strip/disconnect it from diaphysis to stimulate growth (if periosteal attachments are severed, GP proliferation very rapid)

GH is produced by what?

pituitary gland at base of brain aka hypophysis (which is made up of the anterior and posterior pitutiary)

back in the 70s, they gave a treatment to girls growing too tall bc doc's believed they would have a hard time finding husbands. what was treatment?

prescribe high levels of E at early age to stunt growth (but woops it also affects reproductive tract dev and can lead to infertility and uterine cancer)

what stops muscle contraction?

recall signaling began with release of ACh. After, muscle has enzyme that degrades ACh called acetylcholine-esterase so cholinergic R no longer stimulated, which will reestablish interaction b/w DHPR and RyR so no more Ca is released from SR. and Ca is returned inside SR through ATP-dependent active transport pump. no more Ca means troponin returns tropomyosin to blocking BS for myosin on actin and so no more contraction. also, you need E to reverse AP through Na/K-ATPase

describe release of neurotransmitter ACh to turn chemical signal into an electrical signal of AP propagating down sarcolemma of muscle cell (aka how is signal from neuron transmitted into muscle cell?)

signal for contraction comes from neuron that releases ACh at motor-end plate which binds to cholinergic R on muscle cell, which allows Na+ which is abundant outside to enter inside cell and since Na is + charged and membrane is - charged the + ions entering cell cause membrane to be less negative (depolarization) and this change in voltage of membrane stimulates voltage-sensitive channels to also allow Na in, and that stimulus is spread around sarcolemma quickly, which turns chemical signal into electrical signal. in normal state, Na is abundant outside cell and K is abundant inside cell. the channels that open due to ACh allow Na in and K out, which removes the ion gradient, so that's why membrane cannot respond to electrical stimulus for awhile (refractory period) until Na/K-ATPase shuttles 3 Na out and 2 K in to recreate ion gradient and negative charge across membrane

how is the sarcoplasmic reticulum SR of muscle fibers specialized?

stores Ca, which initiates muscle contraction upon its release when AP electricity is transmitted through sarcolemma (recall how it was also Ca that signaled activation of dev in egg)

tension is transmitted in form of what?

tension is transmitted as ELECTRICAL SIGNAL b/w GP and periosteum! physical therapies include electrical stimulation to provide signal to stimulate growth in fracture repair (optimal tension for bone growth and maintenance is related to the presence of electrical current)

muscle fiber/cell is large not only bc they're long and multinucleated but also bc they are wide in diameter! but when muscle contracts, all of the myofibrils inside cell must respond together. how does this happen?

through TT's! they are invaginations of sarcolemma that go deep into muscle. so the electrical AP signal will go across sarcolemma and down through TT and induce voltage-sensitive dihydropyridine receptor (DHPR) to undergo conformational change. DHPR normally interacts with ryanodine R (RyR) on the SR. when AP comes to DHPR, it stops interaction with RyR and opens RyR to release Ca from SR via diffusion since there's very little Ca in sarcoplasm. DHPR and RyR are receptors on SR. recall 2 SR's and a TT make a triad, so on each side of TT, SR makes large sac called terminal cisternae. released Ca binds to troponin-C and induce conformational change so it'll move tropomyosin out of way so myosin head can bind to actin and walk upon it and do power stroke which catalyzes and releases phosphate from ATP. so need new ATP molecule to return to cocked position.

why is IGF-1 aka sulfation factor?

when they add IGF-1 to cartilage cells in culture, it inc deposit of sulfur groups. that tells us IGF-1 induces fixation of sulfation groups in cartilage bc remember cartilage on matrix has chondroitin sulfate

there are factors that affect GP closure?

yes, there are local regulators at each GP, although these are likely influenced by systemic factors (aka whole animal) and events like puberty. whole animal body growth is coordinated/controlled

what is each sarcomere made up of?

-1 sarcomere goes from Z disk to Z disk (Z for zigzag of proteins) -actin is attached to Z disk -myosin is attached to M line (M for middle) -myosin makes up thick filaments -actin makes up thin filament -H zone (H is for heller, German for brighter bc it's brighter than A band only has thick filament) is a part of the A band at the center of the sarcomere that only contains thick (shrinks during muscle contraction) -I band (I for isotropic, all light reflected in same drxn so you can see clearly) is light and only contains thin (shrinks during muslce contraction) -A band (A for anisotropic, scatters light so it's darker) is dark, esp the part not counting H zone, bc that part contains overlapping thick and thin (maintains constant size during muscle contraction) -thick filaments span A band and are composed of protein myosin -thin filaments are attached to Z-line and are composed of 3 proteins: F-actin, tropomyosin, and troponin

importance of ATP (energy) for muscle contraction?

-ATP is absolutely req'd for both contraction and relaxation (so when you lie on couch and parents ask hey what are you doing say im burning ATP LOL) -we need ATP for Na/K-ATPase and ATP for myosin to return to conformation and ATP to pump Ca back inside SR -need ATP to relax! if no ATP, muscles stay contracted (bound to actin). when animal dies, undergoes rigor mortis (nothing gets maintained in dead cells bc no ATP, so Ca that's usually sequestered back into SR due to ATPase won't be, so muscle will stay contracted. but eventually the proteins will get degraded bc animal dies and proteolysis causes muscles to relax)

in conclusion, what are the 3 hormones we use to regulate Ca levels in blood?

-PTH -Vitamin D (calcitriol) -calcitonin

what are myofibrils made up of?

-actin and myosin (and this organization w/n myofibril is what gives muscle the striation/stripes) -myofibrils are made up of sarcomeres, which are the units of contraction

recall bone is Ca storage. how does bone do regulation of calcium and phosphorus?

-all cells req precise concentrations of Ca2+ for proper fxn -main Ca storage is in bone mineral (99% of body Ca aka 1 kg is in bone!) -circulating Ca exchanges with tissue pools and storage pool in bone (blood Ca levels tightly regulated by endocrine system)

testosterone (T)? we didn't go over this slide

-at low dose, stimulates GP cell proliferation -at high dose, stimulates GP closure -GH is req'd for its actions -acts mainly through conversion to E via aromatase: a) male ER deficient mutant: no GP fusion, severe osteoporosis; not responsive to E therapy b) male CYP10 gene mutants: lack aromatase P450; similar effects, but are responsive to E T also has same effects as E. even though chondrocytes do not contain a R for T, T has same effects since it gets converted into E which chondrocytes do have a R for

estrogen (E)? we didn't go over this slide

-direct effects bc ERα and ERβ both present in GP -low levels stimulate chondrocytes & osteoblasts indirectly (via inc IGF-1) -high levels at puberty inhibit growth: dec cartilage growth, inc maturation of GP -also at high levels, inhibit bone resorption by osteoclasts acts both indirectly and directly (direct bc chondrocytes in proliferative zone do contain R for E to bind to)

sex steroids?

-estrogen (E) and testosterone (T) (mostly through E) -affect growth in 2 ways: at low levels, stimulate bone growth. at high levels, induce GP closure -pubertal growth spurt lasts 22 months and accounts for 20% of adult height (very rapid growth spurt before puberty bc there's more secretion of sex steroids but still at low levels. after puberty, stop growing bc now sex steroids secreted at high level) -pubertal growth spurt due mainly to E and T (T converted to E)

let's talk more about myofibrils (within the myofibers)! what are myofibrils made up of?

-form 100s-1000s per fiber -made up of 12-14 aggregated proteins (55% of total muscle protein) -1 thick filament is surrounded by 6 thin filaments, so thin filament interacts with multiple thick filaments and vice versa that's how contraction is coordinated -thick filaments: myosin (each myosin filament has like 300 proteins with heads sticking out like golf clubs. the head interacts with actin and neck undergoes power stroke to do sliding mechanism for contractions) -thin filaments: actin, tropomyosin, and troponin; anchored at Z disk, overlap with thick filaments at A band (actin is found in every cell bc it's part of cytoskeleton. in muscle, actin is organized as F-actin aka filamentous actin which is 2 strands of actin monomers bound together) -intersarcomeric proteins: titin prevents overstretching, nebulin helps align contractile proteins -intrasarcomeric proteins: desmine and α-actinin tie together the myofibrils at the Z disks. costameres anchor proteins to sarcolemma (filamin, vinculin, talin) -collagen: present outside of cell in ECM, takes F from inside cell to outside through endomysium

cardiac muscle?

-found only in heart -network of cells, branched and bound together, also single central nucleus (uninucleated) -has striations (but fainter than skeletal) -short, not that long -have special architecture of organelles like intercalated disk, allows cells to communicate in order to contract together -contraction inherent & rhythmic (no signal to contract, a few cells just do it and since cells are all connected they contract together); rate controlled by autonomic nervous system (CNS) -have lots of mitochondria and blood vessels to supply O2 for aerobic metabolism, and that provides high fatigue resistance so heart beats non-stop throughout life (if cut blood supply even for short time, cardiac cells will die and that's heart stroke)

back to molecular organization! what is a sarcomere again?

-fundamental functional unit of muscle fiber -from Z line to Z line -gets shorter when contract (actin filament pushes in from both sides) -thick and thin filaments that make up sarcomere do NOT change size, it's just that the Z disks get closer to each other as thin filament slides over thick filament, shortening the sarcomere (myosin walks on actin, pulling it closer to M line so the 2 Z disks get closer to each other) -there are mt in b/w fibrils to provide ATP when needed

so what are the 2 methods to stimulate elongation proliferation by manipulating tension b/w periosteum and cartilage at growth plate?

-have one GP close or damaged early and the other GP still grows faster to compensate bc it experiences less tension -periosteum stripping so the bone gets no tension and so bone will elongate more

thyroid hormone (TH)?

-hypothyroidism (too little TH) leads to dec growth AND childish phenotype. recall GH deficiency led to small but adult phenotype so everything had matured (too little TH = chondrocytes remain in quiescent state in resting zone) -like GH, TH also affects bone dev by affecting the cartilage (stimulates chondrocytes in resting zone to start proliferating) -increases width of GP (increases recruitment of resting chondrocytes)

diff types of muscle cells use diff sources and have diff preferences of ATP. what are diff sources of ATP (diff ways muscles get E for contraction)?

-main source of ATP: glycolysis (gets 2 ATP from 1 glucose. muscle req lots of E so they store glucose as glycogen. glycolysis ends in pyruvate, which cannot freely move throughout body) -in absence of O2, pyruvate gets converted into lactic acid to be transported to liver where it's converted back into pyruvate to undergo gluconeogenesis (but too much anaerobic activity leads to lactic acid buildup which leads to fatigue and metabolic problems) -in presence of O2, a lot more efficient! pyruvate undergoes Krebs Cycle and Ox Phos (36 ATP from 1 glucose). if you have O2, can not only use glucose but also use FA's into acetyl CoA through Krebs or aa's to generate ATP -finally, last way to get ATP is through creatine phosphate pathway, which stores a bit of ATP since ATP cannot be stored as itself since it's highly reactive (transfer phosphate from ATP to creatine and make creatine phosphate which is more stable and when you need to regenerate ATP quickly creatine phosphate donates phosphate back to ADP. this is quick way to generate ATP that doesn't req glycolysis or ox phos, but you can't store much via creatine phosphate. but this helps cells maintain a very stable level of ATP. and actually, you can even measure the # of cells in Petri Dish by measuring level of ATP bc each cell will have same constant level!)

what are muscles important for? fxn/function of muscle

-movement -posture (hold joints stable so we can stand) -aa reservoir (muscle is mostly protein) -heat source (contractions produce heat) -blood circulation last but not least: nutritious delicious meat! provides us with high quality protein, iron, zinc, selenium, Vit ABD

DMD gene therapy?

-mutations to DMD happen in the dystrophin gene at exon 49 or 50, a critical part for fxn -recall skeletal muscle cells are multinucleated. not every cell needs fxnal dystrophin gene, only a couple should be able to get heart muscle fxn back to normal -this is huge gene, so it's inefficient to deliver the gene to cell. instead, repair it! muscle cells have many nuclei, and only have to repair a few using CRISPR-CAS9 -mutation occurs at exon and disrupts everything downstream so you're left with half protein that's abnormal. instead of repairing whole thing, skip the mutated exon so you lose a bit of protein but it's still big enough so it doesn't really affect it and the rest of the protein is normal!

myofibrils have contractile proteins which are what?

-myosin: force generation, 30% of muscle protein -actin: myosin ATPase activator, 10% of muscle protein -tropomyosin: regulate myosin-actin interaction -troponin: Ca-dependent mediation of tropomyosin conformation

smooth muscle?

-no striations -spindle-shaped cells with single nucleus in center (uninucleated) -network arrangement of cells (sometimes in diff drxn, longitudinal muscle cells) -regulated by autonomous nervous system (involuntary, not under our conscious control) -surrounding digestive tract, urogenital system, blood vessels (walls of hollow organs)

skeletal muscle is multinucleated bc multiple cells fuse together, so a single fused cell ends up with 100s of nuclei! very few cells do that. recall, what other multinucleated cells are there?

-osteoclasts -specialized macrophages like dendritic cells

Glucocorticoids (GC)?

-part of stress response (continuous stress dec growth) -regulated by GCRH produced in pituitary gland -direct effects: dec chondrogenesis (cartilage formation) -indirect effects: dec GH secretion by pituitary and dec GP mRNA for GHR, GHBP, IGF-1, IGF-1R

technically Vitamin D is not really a vitamin bc we can make it and it doesn't need to be provided in body. how do we make it?

-produced from cholesterol with UV light in skin as dehydrocholesterol -which is activated 1st in liver by 25-hydroxylase -and then in kidney by 1-hydroxylase (stimulated by PTH) -resulting in active Vitamin D aka 1,25-hydroxydehydrocholesterol it can also be consumed in diet in inactive form and then get activated

3) fast-twitch, oxidative-glycolytic (FOG) Type IIa?

-red -intermediate fatigue resistance; recover faster than FG fibers both oxidative and glycolytic capacity -adapted for rapid, repetitive movements, swimming, mid distance running -recruited after SO Type I fibers -intermediate fiber diameters -fast contraction speeds -MYH2: rapid cross-bridge cycling

1) slow-twitch, oxidative (SO) Type I?

-red (bc they contain more mt and blood vessels, which are darker substances) -very fatigue resistant (bc they are slow contractions and don't use a lot of ATP and at same time produce lots of ATP) -slow, repetitive movements (eg postural muscles, marathon running) -depend upon oxidative metabolism and ox phos only happens in mitochondria, thus inc and larger mt and high levels of Mb and surrounded by blood vessels (use ox phos to get 36 ATP from glucose) -dec fiber diameters (to allow O2 diffusion -dec cell size (protein:DNA) -slower contraction speeds (>100sec) -MYH7: slow cross bridge cycling (this myosin heavy chain type 7 is slow contracting type)

what are substances that can block ACh-esterase (aka don't allow muscles to relax)?

-snake venom -chemical warfare -insecticides to prevent insect muscle movement (Dr. Ross's dad saw paralyzed cows bc farmer put insecticide on cow to stop a fly invasion. so the problem was that there's too much ACh stimulating muscle to contract too much w/o relaxation. they fixed it by using atropin drug that inhibits cholinergic R)

skeletal muscle?

-striated (striped) -multinuclear cells with peripheral nuclei (muscle cell = muscle fiber aka myofiber) (skeletal muscle is only type to be multinucleated) -fibers arranged in bundles or fasciculi, which are all bound together and separated by CT: 1) endomysium: surrounds individual fibers (contains collagen fibers for contraction) 2) perimysium: surrounds fiber bundles (contains fat deposits. pulled pork strands are fascicles!) 3) epimysium: surrounds entire muscle (all CT's coalesce into tendon, and that's how force of each cell is transmitted and added to provide strength of full muscle contraction!) all 3 layers of CT contain main blood vessels

what other hormones can affect growth?

-thyroid hormone (TH) -glucocorticoids (cortisol) -sex steroids

myofibrils are also made up of structural proteins. what are they?

-titin: an elastic protein that goes from Z disk to Z disk and holds it to prevent filaments from sliding too far/overstretching -nebulin: like ruler, helps actin filaments align with each other and provide organization to structure -desmine, α-actinin, and vimentin bind actin thin filaments to the Z disks -costameres: anchor proteins to membrane to transduce myofibril contraction inside cell to outside of cell (ex. filamin, vinculin, talin) -dystrophin: one of largest proteins in body! anchors cytoskeleton to collagen in ECM, allowing F transmission from contraction inside cell to outside

what do tropomyosin and troponin do?

-tropomyosin blocks BS for myosin on actin -troponin has 3 parts: 1 binds to tropomyosin, 2nd binds to Ca (troponin C), and 3rd is intermediate -when troponin binds to Ca, it undergoes conformational change and displaces tropomyosin so it no longer blocks BS for myosin on actin -myosin will bind to actin and do power stroke (and it is the thick and thin filaments sliding past each other that causes contraction!)

2) fast-twitch, glycolytic (FG) Type IIb, IIx?

-white -easily fatigued; can go into O2 debt for short periods (fatigue quickly bc they can accumulate too much lactic acid or use up all glucose and only produce 2 ATP from each glucose molecule and be unable to contract anymore) -rapid movements, heavy F generation for strong contractions, sprinting -depend upon anaerobic (glycolytic) metabolism, thus dec mt and Mb (bc don't care about O2 so also they're not really surrounded by blood vessels) but on contrary they will have more glucose stored as glycogen! -inc fiber diameters (so they can have more sarcomeres/myofibrils in order to have stronger F contraction) -fast contraction speeds (inc myosin ATPase); (<7.5msec) -MYH4, MYH1: rapid cross-bridge cycling

diff muscle fiber types are based upon what (muscle fibers are classified based on what 2 main characteristics related to their function)?

1) contraction speed (which depends on myosin isoform. like collagen, myosin encoded by diff genes that give diff traits like contracting faster vs consistently) and 2) metabolic pattern (aka ATP source for contraction) all muscles generate contraction, but muscles do diff things! some sustain contraction all time like postural muscle to maintain posture, others provide high E for sprinting . so not all muscle fibers are the same!

what are the effects of tension (as bone grows, there is close interaction b/w growth plate and periosteum aka the CT membrane surrounding bone)?

1) periosteum is attached to bone (firmly) at epiphyses and (loosely) at diaphysis 2) as bone elongates, periosteum is stretched, creating tension (bc cartilage grows faster) 3) periosteum responds by inc its cell proliferation (and GP slows down) 4) periosteum keeps growing until it overshoots bone length and tension is relieved 5) the GP responds to the reduced tension by increasing its rate of proliferation and ossification, which elongates the bone and starts the entire cycle again

describe the process of muscle contraction (molecular process)

1) release of neurotransmitter acetylcholine ACh from nerve ending across synaptic cleft 2) twitch response to AP 2a) inc membrane potential (-90 mV to -10 mV) 2b) AP (Na+ influx) runs through muscle cell very fast! (electrical signal transmits signal quickly, whereas chemical signal needs time to diffuse) 2c) refractory period is when another AP cannot happen immediately following the 1st one; repolarization (K+ efflux) where balance of K in and Na out is restored 3) intracellular events 3a) propagation of AP throughout plasma membrane (including TT's) 3b) release of Ca from SR into sarcoplasm and myofibrils 3c) Ca combines with troponin and changes conformation of tropomyosin, allowing cross-bridge attachment of myosin heads to actin filament 3d) attachment changes angle b/w head and arm of myosin, forcing filament to slide, shortening the sarcomere 3e) ATP binds to myosin, causing it to release actin. then ATP gets hydrolyzed, which will make it bind to actin and when phosphate is released it does powerstroke 3f) myosin head binds to next binding site on actin, as long as Ca and ATP are present in sufficient concentration (ratchet theory) 3g) when stimulation ends, Ca is sequestered by SR (calsequestrin = transporter) 3h) ATP is therefore req'd for muscle relaxation

what are 3 diff types of muscle? (based on morphology, if they have striations or not, how contractions are controlled, if it's voluntary or involuntary)

1) skeletal (striated and voluntary) 2) smooth (no striations and involuntary. present in wall of every hollow organ like muscle contractions to digest food) 3) cardiac (striated and involuntary. heart muscle. beats autonomously)

based on these 2 characteristics, what are the 3 diff muscle fiber types?

1) slow-twitch, oxidative (SO) Type I (aka red fibers, slow contraction and use O2) 2) fast-twitch, glycolytic (FG) Type IIb, IIx (aka white muscles, fast contraction and use glycolysis) 3) fast-twitch, oxidative-glycolytic (FOG) Type IIa (intermediate fiber type) Type I, IIa, and IIb is the typical order these fibers are called into action. so when neuron needs muscle to move, they first induce contraction with Type I fibers. if higher force req, they induce IIa, and if need very strong contraction then IIb.

how many muscles in body?

600-650 (to compare, 206 bones)

in the sarcomere, which bands change size upon contraction?

A band stays same size and doesn't change bc it's defined by thick filmanet. I band gets smaller bc now there's less area where thin filament is not overlapping thick filmanet. H zone also gets smaller bc now thin filament slides over thick filament and there's less of only thick filament area.

recall we said dystrophin is the largest gene in our genome (2.4 million bases!), so there's high chances of mutations. dystrophin alterations/mutations can result in what?

Duchenne Muscular Dystrophy (DMD) -normal fxn of dystrophin is to bind cytoskeleton of myofibers, so when filaments are sliding/contracting it's transmitted to ECM collagen fibers to transduce F from inside to outside -affected individuals initially fine bc babies don't need strong muscles -but at 3-4 years old, have some delay like not able to hold head up or walk/jump -muscles work fine but movement can't be transmitted = paralysis -heart unable to beat strongly and ribcage unable to produce breathing, so people with DMD die around 25 years old

what ultimately puts a stop to linear bone growth?

GP closure (when it closes depends on age, species, breed, anatomical locaiton) it doesn't matter how much stripping you do to periosteum, if GP closes then no more cartilage so no more growth!

what is main difference that explains great differences/variety in dog size?

IGF gene (genetic diff b/w breeds makes IGF-1 gene more or less active)

GH acts directly or indirectly on bone growth?

ONLY INDIRECT EFFECT it acts indirectly by IGF-1 production at both local in GP and systemic level via liver, and GH has a local effect to prime GP cells to respond to IGF1

YOUTUBE VIDEO: mechanisms of muscle contraction

SARCOMERE ANATOMY -actin aka thick filament are strands of G-actin monomers spirally coiled around to form helix -myosin aka thick filament are rod-shaped elongated proteins with double heads -A band is dark and result of overlapping thick and thin (conversely, both H zone and I band is where they do NOT overlap, causing light appearance) -H zone is only made up of thick -I band is only made up of thin MUSCLE CONTRACTION -each contraction begins with electrochemical AP that arrives at sarcolemma -after release of ACh, sarcolemma is depolarized due to flux of Na into fiber, allowing AP to be transmitted via TT to SR -Ca released from SR's terminal cisternae into sarcoplasm -Ca binds to troponin-C, shifting tropomyosin and exposing myosin BS on actin -in presence of Mg, ATPase is activated and hydroyzes ATp on myosin head, forming ADP and free P. this swivels myosin heads to be on BS on actin, forming cross-bridge -release of P causes myosin head to do powerstroke and slide filament -release of ADP leaves myosin head attached to BS on actin until another ATP binds to myosin head and releases it from actin -as long as Ca remains in sarcoplasm at high concentration, this is continued until full muscle contraction is achieved -one fully contracted, cholinesterase (ACh-esterase) initiates relaxation by breaking down ACh, which repolarizes sarcolemma and TT. -Ca pump uses ATP to return Ca into SR terminal cisternae. without high Ca, actin myosin cross-bridge formation is terminated, tropomyosin blocks BS on actin again, Mg complex is formed with ATP to return myosin head to resting state. passive sliding of myosin filament returns sarcomere to relaxed state!

what is a nutrient AND hormone that is essential in maintaining Ca levels?

Vitamin D (calcitriol) -R in nuclei of target cells -main goal: inc Ca intestinal absorption to deposit into bone (also direct effect on osteoblasts by inc collagen and IGF-1 synthesis) -in cases of Ca deficiency, Vit D can actually inc resorption of bone by osteoclasts! -also inc intestinal absorption of P and inc renal retention of PO4 -stimulated by PTH at kidney and by levels of Ca/P -inactivated at kidney by hydroxylation at 24, allowing Vit D excretion