Physiology Of Muscle MSKS-321 (2024-2025) PDF

MSKS–321 (2024-2025) Physiology Of Muscle Dr. Amir Abushouk Dr. Nadia Elamin 2  Objectives By the end of the lecture the student should be able to: – Describe the different types of muscle fibers and their means of contraction. – Describe the underlying mechanisms i...

MSKS–321 (2024-2025) Physiology Of Muscle Dr. Amir Abushouk Dr. Nadia Elamin 2  Objectives By the end of the lecture the student should be able to: – Describe the different types of muscle fibers and their means of contraction. – Describe the underlying mechanisms in excitation contraction coupling. – Describe the energy supply to muscle and outline the ways it can be disrupted, and the consequences. – Describe the trophic effects of nerves on muscles. – Outline the patterns of denervation and re-innervation of muscles. 3  Types Of Muscles 1. Skeletal muscles: – Have cross-striations, no connections between muscle fibers. – Under voluntary control; contract in response to neural stimulation. 2. Cardiac muscles: – Have cross-striations, with connections between muscle fibers. – The fibers act as one unit or functional syncytium. – Have regular rhythmic contractions modulated by the autonomic nervous system. 3. Smooth muscles: – No cross-striations, can be further subdivided into: Unitary (visceral): functionally syncytial with pacemakers that discharge irregularly. Multiunit type (in the eye): no spontaneous activity and has graded contractile ability. 4  Functions Of Muscles Muscle cells can be excited chemically, electrically, or mechanically to generate an action potential which is transmitted along their cell membranes activation of contraction. Main functions of skeletal muscles: – Production of movement. – Stabilization of the joints. – Maintenance of posture. – Support of soft tissues and internal organs. – Theromgenesis to maintain body temperature. – Storage of nutrient reserves. – Act as sphincters. 5 Skeletal Muscle Organization Muscle Fiber: – A long cylindrical cell, covered by endomysium, with multiple peripheral nuclei. – Each fiber contains several myofibrils. Myofibrils: – Formed of myofilaments: Thick filaments: myosin filaments. Thin filaments: actin, troponin and tropomyosin. Sarcomere: – The functional unit of a muscle fiber. – Part of myofibril between two Z lines. Skeletal Muscle Fiber Sarcolemma: – The cell membrane of the muscle fiber. Sarcoplasm: – Intracellular fluid between myofibrils. Transverse tubule (T-tubule): – Narrow tubes extend at right angles from sarcolemma into the sarcoplasm. Sarcoplasmic reticulum (SR): – Specialized smooth endoplasmic reticulum in sarcoplasm surrounding each myofibrils. Mitochondria: – Large numbers parallel to myofibrils ATP. The Sarcomere Is the functional unit of muscle fiber between two Z lines. Microscopic appearance of the sarcomere shows: – Z line: is a dense fibrous structure formed of filamentous proteins, serves as the anchoring point of actin filaments in a sarcomere. – A (dark) band: spans the entire myosin filament. – I (light) band: only actin filaments (no overlapped myosin filaments). – H zone: the part of myosin filament that is not overlapped by actin filaments. – M line: middle of the sarcomere, anchors and stabilizes myosin during muscle contraction. 8  Proteins Of Muscle Myofibrils are built of different proteins: 1. Contractile proteins: Produce contraction. Myosin and actin. 2. Regulatory proteins: Turn contraction on and off. Troponin and tropomyosin. 3. Structural proteins: Provide proper alignment and elasticity. Titin, desmin, dystrophin and actinin.  Contractile Proteins Myosin: – Forms thick filaments; hold in place by the M line proteins. – Myosin molecule has a tail and 2 heads: 2 heavy chains wrap spirally form tail. Each heavy chain has one end connected to the myosin head. – Myosin heads (cross bridges) have ATPase activity and actin binding site. Actin: – Two chains of actin form a long double helix linked to Z discs. – Contains myosin-binding site. Regulatory Proteins Troponin and tropomyosin form the thin filaments with actin molecules. Tropomyosin: – Long filaments in the groove between actin chains covering myosin-binding site on actin molecules in relaxed muscle. Troponin: – Small globular units located at intervals along the tropomyosin molecules. – Composed of three subunits: Troponin T: binds to tropomyosin. Troponin I: binds to actin inhibits the interaction of myosin with actin. Troponin C: binds to calcium ions helps to initiate contraction. Structural Proteins Titin (one of the largest proteins): – Attaches myosin molecules to Z disk; holds myosin and actin filaments in place provides elasticity and prevents overstretching of sarcomere (Springy). Actinin: binds actin filaments to Z lines. Desmin: helps to maintain structural and mechanical integrity of muscle by binding Z lines to plasma membrane. Dystrophin–glycoprotein Complex: – Dystrophin connects actin to sarcolemma (dystroglycan, sarcoglycan,..) transmits tension generated to tendon. – Mutations in dystrophin muscle dystrophy: Duchenne muscle dystrophy (DMD). Becker muscular dystrophy (BMD). Cross-Bridge Cycle During rest myosin head is found in its high-energy conformation (bound to ADP and Pi) but the regulatory proteins (tropomyosin and troponin) normally inhibit the interaction between myosin and actin. When Ca2+ binds to troponin changes in tropomyosin-troponin complex  uncovers actin active sites cross bridging with myosin head. When myosin head binds to actin in the thin filament power stroke. 13 Interaction Between “Activated” Actin Filament and Myosin Cross-Bridges The Cross-Bridge Cycle (“Walk-Along” Theory of Contraction) Cross-Bridge Cycle After cross bridging or binding of myosin to actin: Power stroke: – Stored energy in myosin heads is used to pull actin filament toward M line; and ADP is released from myosin heads low-energy form of myosin head. Unbinding of myosin and actin: – Myosin heads remain bound to actin till new ATP binds to the myosin head. – When new ATP binds to myosin heads conformational change myosin heads detach from actin. Cocking of the myosin head: – Hydrolysis of ATP by myosin head releases energy and forces myosin head into high-energy conformation (bound to ADP and Pi) cycle can then be repeated. 15 Excitation-contraction Coupling Referred to the sequence of events that links action potential generated in a muscle cell by the motor neuron with the muscle contraction. DHP receptor: Dihydropyridine voltage gated receptor is linked to Ca2+ release channels (Ryanodine channels). 16  Excitation-contraction Coupling DHP receptor Ryanodine receptor Depolarization of the muscle membrane and T tubules calcium ions release from SR muscle contraction. 17 Calcium ions are pumped back into the SR and stored till a new AP arrives; this removal of Muscle Contraction Myosin heads pull on the thin filaments in cross bridge cycles. When thin filaments slide inward: – Z Discs come close each other. – Sarcomeres shorten muscle fiber shortens. – Tension is generated by the contracting muscle. The degree of overlap between actin and myosin filaments determines the developed tension. Muscle Relaxation Is an active process that requires ATP to: – Pump calcium actively back to sarcoplasmic reticulum by Ca2+ ATPase. – Unbind myosin head from actin. During rest troponin returns to original site allowing tropomyosin to cover the myosin binding sites on actin. ATP is required for detachment of the cross bridges. 19 Energy Supply To The Muscle During muscle contraction energy is required for: 1. Movement of myosin heads; or cross-bridges pull actin filaments. 2. Pumping calcium into sarcoplasmic reticulum after contraction. 3. Sodium and potassium pumping through muscle fiber membrane to maintain propagation of muscle fiber action potentials. The immediate sources of energy are: Energy-rich phosphate compound; Creatine phosphate system (Phosphocreatine (PCr)). ATP formed by metabolism of carbohydrates and lipids: 1. Glycolytic system (Anaerobic glycolysis). 2. Oxidative system (Oxidative phosphorylation). 20 Energy Supply To The Muscle Energy Supply To The Muscle Energy required for muscle contraction is obtained from: 1. Phosphocreatine: – At rest, ATP transfers its phosphate to creatine phosphorylcreatine. – During exercise, phosphorylcreatine is hydrolyzed at the junction between myosin heads and actin ATP from ADP allows contraction to continue. – Is a ready and rapid source of renewal of ATP during contraction. 2. Anaerobic glycolysis: – Each molecule of glucose 2 ATP (Pyruvic acid lactic acid). 3. Oxidative phosphorylation: – Complete break down of glucose, fatty acids or amino acids within the mitochondria (aerobic) much more energy than anaerobic systems. – Needs oxygen. 22 Disrupted Energy Supply To Muscle Metabolic myopathies: – Mutations in genes that code for enzymes involved in metabolism of fats, carbohydrates, and proteins and production of ATP (e.g., McArdle syndrome). – Present with intolerance to exercise and possibility of muscle damage because of accumulation of toxic metabolites. Rigor: – A state of rigidity of skeletal muscles caused by depletion of energy supply (ATP)  myosin heads attached to actin in an abnormal, fixed and resistant way. Rigor mortis: – The rigidity that occurs hours after death due to loss of all ATP (muscles are locked in place and become quite stiff to touch). – Muscles remain in rigor till proteins autolysis occurs 15-25 hours. 23  Types Of Skeletal Muscle Fibers Muscle fibers can be classified according to their twitch duration into: 1. Slow fibers (Type I or red oxidative fibers): – Small fibers diameter and small nerve fibers. – More blood supply, more mitochondria. – More myoglobin (MB is red pigment). – Slow prolonged contraction. – Slow fatigue (fatigue resistant). 2. Fast fibers (Type II): I. Fast glycolytic fibers (Type II- B or white fibers): Large diameter, large glycogen reserves, less mitochondria, less blood supply and MB. Fast strong contraction very quickly but fatigue easily. II. Fast oxidative or intermediate fibers (Type II-A): Mid-sized, more myoglobin, more capillaries than type II- B and slower to fatigue. The proportion of type I and type II fibers varies in different muscles, with greater proportions of type I fibers in postural muscles (more suited to prolonged activity, more efficient and have a greater 24 dependence on oxidative metabolism of fatty acids and glycogen than type II fibers).  Types Of Skeletal Muscle Fiber Slow-twitch Oxidative Fast-twitch Oxidative Fast-twitch Glycolytic (Red Muscle) (Red Muscle) (White Muscle) Type I Type II- A Type II- B Speed of development of Slowest Intermediate Fast maximum tension Myosin ATPase activity Slow Fast Fast Diameter Small Medium Large Contraction duration Longest Short Short Ca-ATPase activity in SR Moderate High High Endurance Fatigue Resistant Fatigue Resistant Easily Fatigued Use Most used-posture Standing-walking Least used-jumping Metabolism Oxidative-Aerobic Become more oxidative Glycolytic; more anaerobic with endurance training than Fast-twitch oxidative Capillary density High Medium Low Mitochondria Numerous Moderate Few Colour Dark red (Myoglobin) Red Pale Muscle Atrophy Muscles are continuously remodeled to matched the required function. Remodeling involve change in diameter, length, vascularity and strength. When a muscle is not used for a long time, its mass declines (Atrophy) because the rate of protein degradation exceeds the rate of replacement: – The muscle fibers become smaller and weaker. – Contractile proteins in each muscle fiber decrease. – The number of muscle fibers may remain constant. Muscle atrophy can result from: – Chronic diseases. – Disuse atrophy (plaster or cast). – Denervation atrophy (after injury of the nerve supply). – Muscular dystrophy. 26 Denervation And Re-innervation Of Muscles Denervation: when a muscle loses its nerve supply loss of contractile signals that are required to maintain normal muscle size and function: – Atrophy begins immediately. – In the late stages of denervation atrophy, most of the muscle fibers are replaced by fibrous and fatty tissues. The remaining fibers have few or no contractile properties and less capability of regenerating myofibrils. – The fibrous tissues that replace the muscle fibers during denervation atrophy also tends to continue shortening contracture. Re-innervation: muscle grows back rapidly, and full return of function can occur in about 3 months. Capability of functional return becomes less, with no function return after 1 to 2 years. 27  Muscle Growth And Hypertrophy Muscle growth and hypertrophy occur during: – Growth and puberty. – Regeneration after muscle injury. – Regular training e.g., weightlifters (8-10 weeks). – Re-innervation after denervation trophic effects of nerves on muscles. Growth and trophic factors act by increasing: – Synthesis of new contractile proteins in myofibrils. – Muscle diameter mainly fast glycolytic fibers. – Mitochondria glycolytic enzymes, and glycogen reserves. – Vascularity. – New sacromeres may be added at the end of muscle fibers with stretching exercise. – Number of muscle fibers may rarely increase with extreme muscle force hyperplasia. References