REMODELING OF MUSCLE TO MATCH FUNCTION- Self learning, Lecture # 6, page # 90 Ch # 6 UNIT 2.

• Skeletal muscles continuously remodel themselves to meet the functional demands placed on them.
• This remodeling helps the muscles adapt to changing levels of activity and workload.
• During remodeling, several muscle properties can change:
  • Muscle diameter (thickness) can increase or decrease.
  • Muscle length can change.
  • Muscle strength can increase or decrease.
  • Blood (vascular) supply to the muscle can be altered.
  • The types of muscle fibers can also change slightly.
• These changes allow the muscle to perform its required function more effectively.
• Muscle remodeling is often a rapid process.
• Significant changes can occur within a few weeks.
• Experiments in animals have shown that the contractile proteins of some small, highly active muscles can be completely replaced in as little as 2 weeks.
• This demonstrates that skeletal muscle is a highly adaptable tissue with continuous protein turnover.

KEY CONCEPT

• Skeletal muscles continuously remodel to match their functional demands.
• Remodeling can change muscle diameter, length, strength, blood supply, and even muscle fiber type.
• These adaptations help muscles perform their required functions more efficiently.
• Muscle remodeling occurs rapidly, often within a few weeks.
• In some small, active muscles, contractile proteins can be replaced in as little as 2 weeks.

Muscle Hypertrophy and Muscle Atrophy

• Muscle hypertrophy means an increase in the total mass (size) of a muscle.
• Muscle atrophy means a decrease in the total mass (size) of a muscle.

Muscle Hypertrophy

• Almost all muscle hypertrophy occurs because the number of actin and myosin filaments increases within each muscle fiber.
• As a result, each individual muscle fiber becomes larger.
• This enlargement of a muscle fiber is called fiber hypertrophy.
• Hypertrophy occurs much more when the muscle contracts against a load (resistance).
• Only a few strong muscle contractions each day are enough to produce significant hypertrophy within 6–10 weeks.
• The exact mechanism by which forceful contraction causes hypertrophy is not completely understood.
• During hypertrophy:
  • The rate of synthesis of muscle contractile proteins increases greatly.
  • More actin and myosin filaments are formed inside the myofibrils.
  • The number of these filaments may increase by as much as 50%.
• In some hypertrophying muscles:
  • Existing myofibrils have been observed to split and form new myofibrils.
  • However, the importance of this process in normal muscle enlargement is still uncertain.
• Along with the increase in myofibril size:
  • The muscle’s energy-producing enzyme systems also increase.
  • Glycolytic enzymes increase especially, allowing the muscle to produce ATP rapidly during short, forceful contractions.

Muscle Atrophy

• When a muscle is not used for many weeks, it gradually becomes smaller.
• This decrease in muscle size is called muscle atrophy.
• During atrophy:
  • Contractile proteins are broken down faster than they are replaced.
  • As a result, muscle mass decreases.
• Much of this protein breakdown occurs through the ATP-dependent ubiquitin–proteasome pathway.
• Proteasomes are large protein complexes that:
  • Break down damaged or unnecessary proteins.
  • They do this by proteolysis, which is the chemical breakdown of peptide bonds.
• Ubiquitin is a regulatory protein that:
  • Tags (labels) proteins for destruction.
  • These tagged proteins are then degraded by proteasomes.

KEY CONCEPT

• Muscle hypertrophy is an increase in muscle size, while muscle atrophy is a decrease in muscle size.
• Hypertrophy occurs mainly because more actin and myosin filaments are added to each muscle fiber, producing fiber hypertrophy.
• Resistance (loaded) contractions stimulate hypertrophy, and noticeable changes can occur within 6–10 weeks.
• During hypertrophy, contractile protein synthesis increases, myofibrils enlarge, glycolytic enzymes increase, and myofibrils may occasionally split to form new ones.
• Muscle atrophy develops when muscles remain unused for weeks because protein degradation exceeds protein replacement.
• The ATP-dependent ubiquitin–proteasome pathway is a major mechanism responsible for protein breakdown during muscle atrophy.

Adjustment of Muscle Length

• Muscles can remodel their length to match the functional demands placed on them.

When a Muscle Is Stretched

• When a muscle is stretched beyond its normal length, another type of muscle hypertrophy occurs.
• This stretching stimulates the formation of new sarcomeres.
• New sarcomeres are added at the ends of the muscle fibers, where the fibers attach to the tendons.
• In newly developing muscle, new sarcomeres can be added as rapidly as several per minute.
• This demonstrates that muscle length can adapt very quickly.

When a Muscle Remains Shortened

• When a muscle remains continuously shorter than its normal length, the opposite change occurs.
• Sarcomeres at the ends of the muscle fibers gradually disappear.
• This reduces the overall length of the muscle fiber.

Purpose of Muscle Length Adjustment

• By adding sarcomeres during stretching and removing sarcomeres during prolonged shortening, muscles are continuously remodeled.
• This remodeling maintains the appropriate muscle length.
• Maintaining the proper length allows the muscle to contract efficiently and produce normal force.

KEY CONCEPT

• Muscles continuously adjust their length to meet functional requirements.
• Stretching a muscle beyond its normal length stimulates the addition of new sarcomeres at the ends of muscle fibers where they attach to tendons.
• In developing muscle, several new sarcomeres can be added each minute.
• When a muscle remains shortened for a long time, sarcomeres at the ends of the muscle fibers disappear.
• The addition and removal of sarcomeres help maintain the optimal muscle length for effective contraction.

Satellite Cells and Muscle Repair

• Skeletal muscle contains special adult stem cells called satellite cells.
• Under normal conditions, satellite cells remain inactive (quiescent).
• When muscle fibers are damaged by:
  • Normal daily activity, or
  • Muscle injury,
  satellite cells become activated. (Fig. 6.16)
• After activation, satellite cells begin to multiply (proliferate).
• Following several cycles of proliferation, they differentiate into muscle cells.
• These differentiated cells then fuse with the damaged muscle fibers at the site of injury.
• This process repairs the injured muscle fibers.
• Satellite cells are essential for:
  • Maintaining normal muscle homeostasis.
  • Muscle hypertrophy (increase in muscle size).
  • Muscle regeneration after injury.

Satellite Cells and Aging

• As people age, the number of satellite cells decreases.
• Their ability to repair damaged muscle fibers also declines.
• This reduction may contribute to the age-related loss of muscle mass, known as sarcopenia.
• Exercise activates satellite cells.
• Therefore, regular exercise may help prevent or reverse some of the age-related loss of muscle mass.

KEY CONCEPT

• Satellite cells are adult stem cells found in skeletal muscle.
• They normally remain inactive but become activated after muscle damage (Fig. 6.16).
• Activated satellite cells proliferate, differentiate, and fuse with damaged muscle fibers to repair them.
• Satellite cells are essential for normal muscle maintenance, muscle hypertrophy, and muscle regeneration after injury.
• Aging reduces the number and repair capacity of satellite cells, contributing to sarcopenia.
• Exercise stimulates satellite cells and may reduce or reverse some age-related muscle loss.

Hyperplasia of Muscle Fibers

• Under rare conditions of extremely high muscle force generation, the number of muscle fibers may increase slightly.
• This increase occurs in addition to the enlargement (hypertrophy) of existing muscle fibers.
• The increase in the number of muscle fibers is called muscle fiber hyperplasia.
• Fiber hyperplasia is uncommon.
• Even when it occurs, the increase in muscle fiber number is usually only a few percent.
• The main mechanism of fiber hyperplasia is the linear splitting of previously enlarged (hypertrophied) muscle fibers.
• As an enlarged muscle fiber splits, new muscle fibers are formed, leading to a small increase in the total number of muscle fibers.

KEY CONCEPT

• Muscle fiber hyperplasia is the increase in the number of muscle fibers.
• It occurs only under rare conditions of extreme muscle force generation.
• The increase in fiber number is usually small (only a few percent).
• Hyperplasia occurs in addition to muscle hypertrophy.
• The primary mechanism is the linear splitting of previously enlarged (hypertrophied) muscle fibers.

Muscle Denervation Causes Rapid Atrophy

• Denervation means loss of the nerve supply to a muscle.
• When a muscle loses its nerve supply, it no longer receives the nerve impulses (contractile signals) needed to maintain its normal size.
• As a result, muscle atrophy begins almost immediately.

Early Changes After Denervation

• Within about 2 months, degenerative changes begin to appear in the muscle fibers.
• If the nerve grows back quickly, the muscle can recover completely.
• Full return of muscle function may occur within about 3 months.
• After this period:
  • The chance of functional recovery gradually decreases.
  • After 1–2 years, no further functional recovery usually occurs, even if the nerve regrows.

Late Changes in Denervation Atrophy

• In the final stage of denervation atrophy:
  • Most muscle fibers are destroyed.
  • They are replaced by fibrous tissue and fatty tissue.
• The remaining muscle fibers:
  • Consist mainly of a long cell membrane with a row of muscle cell nuclei.
  • Have few or no contractile properties.
  • Have little or no ability to regenerate myofibrils, even if the nerve later regrows.

Contracture

• The fibrous tissue that replaces muscle fibers continues to shorten for many months.
• This progressive shortening is called contracture.
• Contracture can cause severe disability and deformity if it is not prevented.

Prevention of Contracture

• One of the major goals of physical therapy is to prevent contractures in muscles undergoing denervation atrophy.
• This is achieved by:
  • Daily stretching of the affected muscles.
  • Using splints or other appliances that keep the muscles stretched during the atrophying process.

KEY CONCEPT

• Denervation causes rapid muscle atrophy because the muscle no longer receives the nerve impulses required to maintain its size.
• Degenerative changes appear after about 2 months.
• If the nerve regrows early, complete recovery may occur within about 3 months, but the chance of recovery declines with time and is usually absent after 1–2 years.
• In advanced denervation, muscle fibers are replaced by fibrous and fatty tissue, and the remaining fibers have little or no contractile or regenerative ability.
• Fibrous tissue gradually shortens, producing contracture.
• Daily stretching and supportive devices are essential to prevent contractures during denervation atrophy.

Recovery of Muscle Contraction in Poliomyelitis: Development of Macromotor Units

• In poliomyelitis (polio), some nerve fibers supplying a muscle are destroyed, while others remain intact.
• The remaining healthy nerve fibers produce new branches (axons).
• These new axons reinnervate many of the previously paralyzed muscle fibers.
• As a result, very large motor units are formed, called macromotor units.
• A macromotor unit may contain up to five times the normal number of muscle fibers supplied by one spinal motoneuron.
• Formation of macromotor units:
  • Restores part of the muscle’s strength.
  • Reduces the precision (fine control) of muscle movements, because one nerve now controls many more muscle fibers.

KEY CONCEPT

• After partial nerve damage in poliomyelitis, surviving nerve fibers sprout new axons to reinnervate paralyzed muscle fibers.
• This forms macromotor units that are much larger than normal.
• Macromotor units improve muscle strength but reduce fine motor control.

Rigor Mortis

• Within a few hours after death, all the skeletal muscles become stiff and contracted.
• This condition is called rigor mortis.
• During rigor mortis:
  • Muscles contract and become rigid even without action potentials.
• The main cause is the complete depletion of ATP.
• ATP is required to detach myosin cross-bridges from actin during muscle relaxation.
• Without ATP, the cross-bridges remain attached, so the muscles stay contracted.
• Rigor mortis lasts until the muscle proteins begin to break down, usually 15–25 hours after death.
• This breakdown is believed to occur because of autolysis, in which lysosomal enzymes digest the muscle proteins.
• Higher temperatures accelerate all of these processes, causing rigor mortis to develop and disappear more quickly.

KEY CONCEPT

• Rigor mortis is the stiffness of muscles that develops a few hours after death.
• It occurs because ATP is depleted, preventing separation of actin and myosin cross-bridges.
• Rigor ends after 15–25 hours when muscle proteins are digested by lysosomal enzymes.
• Higher temperatures speed up both the onset and disappearance of rigor mortis.

Muscular Dystrophy

• Muscular dystrophies are inherited disorders that cause:
  • Progressive muscle weakness.
  • Degeneration of muscle fibers.
  • Replacement of muscle tissue by fatty tissue and collagen.

Duchenne Muscular Dystrophy (DMD)

• One of the most common muscular dystrophies is Duchenne muscular dystrophy (DMD).
• DMD affects only males because it is inherited as an X-linked recessive disorder.
• DMD is caused by a mutation in the gene that produces dystrophin.
• Dystrophin is a protein that:
  • Links actin filaments to proteins in the muscle cell membrane.
  • Forms a connection between the intracellular contractile apparatus and the extracellular connective tissue matrix.

Effects of Dystrophin Deficiency

• Absence or abnormal dystrophin destabilizes the muscle cell membrane.
• It also activates several pathophysiological changes, including:
  • Abnormal intracellular Ca²⁺ handling.
  • Reduced ability to repair the muscle cell membrane after injury.
• One major effect is increased membrane permeability to Ca²⁺.
• As a result:
  • Extracellular Ca²⁺ enters the muscle fiber.
  • This activates intracellular enzymes.
  • These enzymes cause proteolysis (protein breakdown).
  • Eventually, muscle fibers degenerate and are destroyed.

Clinical Features of DMD

• Muscle weakness begins in early childhood.
• The weakness progressively worsens.
• Most patients require a wheelchair by about 12 years of age.
• Many patients die from respiratory failure before the age of 30 years.

Becker Muscular Dystrophy (BMD)

• Becker muscular dystrophy (BMD) is also caused by mutations in the dystrophin gene.
• Compared with DMD:
  • Symptoms begin later.
  • Disease progression is slower.
  • Survival is longer.
• DMD and BMD together affect approximately 1 in every 5600–7700 males between 5 and 24 years of age.
• Currently, there is no effective treatment for DMD or BMD.
• However, understanding their genetic basis has created the potential for future gene therapy.

KEY CONCEPT

• Muscular dystrophies are inherited diseases that cause progressive muscle weakness and replacement of muscle fibers by fat and collagen.
• Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene and affects only males.
• Dystrophin connects the contractile apparatus to the muscle cell membrane and helps maintain membrane stability.
• Loss of dystrophin increases Ca²⁺ entry into muscle fibers, leading to enzyme activation, proteolysis, and muscle fiber destruction.
• DMD begins in early childhood, progresses rapidly, often requires wheelchair use by about 12 years of age, and commonly leads to respiratory failure before 30 years of age.
• Becker muscular dystrophy (BMD) is a milder form with later onset and longer survival.
• Although no effective treatment currently exists, advances in genetics offer the possibility of future gene therapy.

prepare and made by Dr sheen