Lecture 1 â Skeletal Muscle: Structure/Function ⢠Mechanisms and ...
Lecture 1 – Skeletal Muscle: Structure/Function • •
Mechanisms and treatments for muscle wasting and weakness Significant problems of unmet clinical needs
Why understanding skeletal muscle physiology is important: • Restoring muscle function after illness of injury • Slowing the progression of age-related muscle wasting and weakness o Muscle strength deteriorates, and capacity to perform decreases • Promoting successful muscle repair after injury • Sport Physiology for improving muscle performance Clinical Features of DMD • Normal muscle cross section – tightly packed muscle fibres o Force producing capacity of the muscle should be fairly strong • DMD – variable, infiltration of connective tissue and fat that affects power and strength o Missing a protein, muscle doesn’t repair as they should o Eventually leads to complete loss of muscles • Between 3 and 6 years the gait becomes lordotic and waddling • Enlargement of the calf, gluteal, lateral vastus, detltoidand infraspinatus muscles • Muscles of the lower extremity and torso appear more affected than those of the upper extremity • Between 6 and 11 years of age, strength of limb and torso muscles decreases linearly Tissue Engineered Skeletal Muscle • Can grow muscle fibres in a lab – tissue fibres • Possibility of creating artificial meat sources through muscle precursors • Take muscle out, grow in dish, return to disease/compromised tissue that can potentially graft Neuromuscular Junction • Synapse between a motor neuron and a skeletal muscle fibre • Nerves tell the muscle what to do • NMJ between motor neuron and muscle fibre o Important aspect in terms of muscle fatigue • AP – propagation to the terminal button of a motor neuron • Opening of VG Ca2+ channels and entry of Ca2+ • Ca2+ triggers the release of ACh • ACh diffuses across the cleft and binds with receptors on the motor end plate • Opening of cation channels Na+ in, K+ out • End-plate potential results, initiates an AP that propagates throughout fibre • ACh destroyed by AChE – terminates the response Muscle Structure • Generally, most muscles have a proximal (origin) and distal (insertion) end • Muscle is made up of bundles (fascicles) of fibres • Fibre = cell • Each fibre is made up of many myofibrils • The myofibrils appear striated because of the alternating dark A and light I bands
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o Overlap of thick and thin filaments (myosin and actin) Arranged in sarcomere – basic contractile unit of muscle Demarcated by Z-lines Myofibrils occupy 80% of the fibre volume 100s to 1000s of myofibrils in each fibre o Muscle have to do greater work, these can grow and hypertrophy to make a larger muscle Approximately 1-2um in diameter The myofibrils are maintained in transverse register across the cell giving rise to the striation pattern Tissue/tendon acts as a spring – elastic component Contribute to force/resistance to lift a load Sarcomere demarcated by the Z-lines and the overlap of thick and thin filaments Filaments slide between one another o Length of filaments doesn’t change o Allows cross bridge activity to occur Z line moves towards the midline Muscles always have the desire to shorten o The contractile units are all moving towards the midline
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Sarcoplasmic reticulum – internal stores of calcium When an AP is generated from the NMJ and travels along the surface of the muscle fibre, down the t-tubule network, it changes the electrical potential to release Ca2+ from the SR to allow muscle contraction to occur When a muscle wants to relax the calcium is taken back up by the SR Different cells will have different distributions of mitochondria
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Proteins help keep the structure together when the muscle is activated and stretched Muscle is help together by cytoskeletal proteins Critical in organisation and stability of muscle fibres DMD is missing one of the proteins – dystrophin Cytoskeletal proteins are critical in the organisation and stability of the muscle fibres
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Key protein myosin There are two binding sites o Binding site for actin – myosin head binds to actin filament o Other binding site is for ATP for active cross bridge cycling
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Hinge region – gives enormous level of flexibility o When myosin head binds to an actin head, it can pull sarcomere towards the midline o Hinge region allows myosin to swing and bind to different sites on actin
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Key protein actin Actin molecules twist into a helical array At rest, tropomyosin covers the binding site preventing myosin head from attaching o Muscle is relaxed because of steric hindrance Troponin is the binding site for Ca2+ o Ca2+ binds to troponin and tropomyosin shifts out of the way, myosin binds to actin Ca2+ is taken away from troponin, tropomyosin shifts back to cover sites on actin and the muscle relaxes
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Muscle Structure • Myofibrils occupy 80% of the fibre volume • Maintained in transverse register across the cell giving rise to the striation pattern • The arrangement of fibres relative to the axis of the force generation • Most fibres insert obliquely into the tendon – resembles a feather arrangement – pinnation • Allows more fibres to be packed in which increases the effective muscle cross-sectional area • • • • • •
Muscles differ in the way their fibres are packed into musculature Fusiform – fibres run length of muscles, one tended to another in a “straight line” Unipinnate – central tendon with fibres running to tendon Bipinnate – central tendon with fibre running to the midline Muscle A has greater cross section because it has more fibres running through Force proportional to muscle area A > B
Force • Force production is proportional to muscle CSA • Muscles are designed for a specific function – architectural specialisation o Muscles for fine control – dexterity o Muscles for force and power output o Eg/ bicep fusiform – fibre length is almost the same as muscle length Types of Contraction • Muscles have a tendency to shorten o Movement of sarcomeres means it will shorten • Isometric – force being produced by the muscle is the same as the load so there is no change in length • Miometric = concentric = shortening o Light load – force produced by the muscle exceeds the load and the muscle shortens • Pliometric = eccentric = lengthening o Heavy load – load exceeds the muscle force and the muscle with lengthen Types of Muscle Actions • Shortening – if the force developed by the muscle > the load on the muscle • Isometric – when the force developed by the muscle and the load are equivalent, or the load is immovable • Lengthening – when the load on the muscle > the force developed by the muscle
Mechanisms and treatments for muscle wasting and weakness Significant problems of unmet clinical needs
Why understanding skeletal muscle physiology is important: • Restoring muscle function after illness of injury • Slowing the progression of age-related muscle wasting and weakness o Muscle strength deteriorates, and capacity to perform decreases • Promoting successful muscle repair after injury • Sport Physiology for improving muscle performance Clinical Features of DMD • Normal muscle cross section – tightly packed muscle fibres o Force producing capacity of the muscle should be fairly strong • DMD – variable, infiltration of connective tissue and fat that affects power and strength o Missing a protein, muscle doesn’t repair as they should o Eventually leads to complete loss of muscles • Between 3 and 6 years the gait becomes lordotic and waddling • Enlargement of the calf, gluteal, lateral vastus, detltoidand infraspinatus muscles • Muscles of the lower extremity and torso appear more affected than those of the upper extremity • Between 6 and 11 years of age, strength of limb and torso muscles decreases linearly Tissue Engineered Skeletal Muscle • Can grow muscle fibres in a lab – tissue fibres • Possibility of creating artificial meat sources through muscle precursors • Take muscle out, grow in dish, return to disease/compromised tissue that can potentially graft Neuromuscular Junction • Synapse between a motor neuron and a skeletal muscle fibre • Nerves tell the muscle what to do • NMJ between motor neuron and muscle fibre o Important aspect in terms of muscle fatigue • AP – propagation to the terminal button of a motor neuron • Opening of VG Ca2+ channels and entry of Ca2+ • Ca2+ triggers the release of ACh • ACh diffuses across the cleft and binds with receptors on the motor end plate • Opening of cation channels Na+ in, K+ out • End-plate potential results, initiates an AP that propagates throughout fibre • ACh destroyed by AChE – terminates the response Muscle Structure • Generally, most muscles have a proximal (origin) and distal (insertion) end • Muscle is made up of bundles (fascicles) of fibres • Fibre = cell • Each fibre is made up of many myofibrils • The myofibrils appear striated because of the alternating dark A and light I bands
• • • • • •
• • • •
• •
• •
o Overlap of thick and thin filaments (myosin and actin) Arranged in sarcomere – basic contractile unit of muscle Demarcated by Z-lines Myofibrils occupy 80% of the fibre volume 100s to 1000s of myofibrils in each fibre o Muscle have to do greater work, these can grow and hypertrophy to make a larger muscle Approximately 1-2um in diameter The myofibrils are maintained in transverse register across the cell giving rise to the striation pattern Tissue/tendon acts as a spring – elastic component Contribute to force/resistance to lift a load Sarcomere demarcated by the Z-lines and the overlap of thick and thin filaments Filaments slide between one another o Length of filaments doesn’t change o Allows cross bridge activity to occur Z line moves towards the midline Muscles always have the desire to shorten o The contractile units are all moving towards the midline
• •
Sarcoplasmic reticulum – internal stores of calcium When an AP is generated from the NMJ and travels along the surface of the muscle fibre, down the t-tubule network, it changes the electrical potential to release Ca2+ from the SR to allow muscle contraction to occur When a muscle wants to relax the calcium is taken back up by the SR Different cells will have different distributions of mitochondria
• • • • •
Proteins help keep the structure together when the muscle is activated and stretched Muscle is help together by cytoskeletal proteins Critical in organisation and stability of muscle fibres DMD is missing one of the proteins – dystrophin Cytoskeletal proteins are critical in the organisation and stability of the muscle fibres
• •
Key protein myosin There are two binding sites o Binding site for actin – myosin head binds to actin filament o Other binding site is for ATP for active cross bridge cycling
•
Hinge region – gives enormous level of flexibility o When myosin head binds to an actin head, it can pull sarcomere towards the midline o Hinge region allows myosin to swing and bind to different sites on actin
• • •
Key protein actin Actin molecules twist into a helical array At rest, tropomyosin covers the binding site preventing myosin head from attaching o Muscle is relaxed because of steric hindrance Troponin is the binding site for Ca2+ o Ca2+ binds to troponin and tropomyosin shifts out of the way, myosin binds to actin Ca2+ is taken away from troponin, tropomyosin shifts back to cover sites on actin and the muscle relaxes
• •
Muscle Structure • Myofibrils occupy 80% of the fibre volume • Maintained in transverse register across the cell giving rise to the striation pattern • The arrangement of fibres relative to the axis of the force generation • Most fibres insert obliquely into the tendon – resembles a feather arrangement – pinnation • Allows more fibres to be packed in which increases the effective muscle cross-sectional area • • • • • •
Muscles differ in the way their fibres are packed into musculature Fusiform – fibres run length of muscles, one tended to another in a “straight line” Unipinnate – central tendon with fibres running to tendon Bipinnate – central tendon with fibre running to the midline Muscle A has greater cross section because it has more fibres running through Force proportional to muscle area A > B
Force • Force production is proportional to muscle CSA • Muscles are designed for a specific function – architectural specialisation o Muscles for fine control – dexterity o Muscles for force and power output o Eg/ bicep fusiform – fibre length is almost the same as muscle length Types of Contraction • Muscles have a tendency to shorten o Movement of sarcomeres means it will shorten • Isometric – force being produced by the muscle is the same as the load so there is no change in length • Miometric = concentric = shortening o Light load – force produced by the muscle exceeds the load and the muscle shortens • Pliometric = eccentric = lengthening o Heavy load – load exceeds the muscle force and the muscle with lengthen Types of Muscle Actions • Shortening – if the force developed by the muscle > the load on the muscle • Isometric – when the force developed by the muscle and the load are equivalent, or the load is immovable • Lengthening – when the load on the muscle > the force developed by the muscle
