Muscular Dystrophies

Duchenne Muscular Dystrophy (DMD)

Duchenne muscular dystrophy is a severe, inherited muscle disorder characterized by progressive degeneration of skeletal and cardiac muscle. It is the most common form of muscular dystrophy and is inherited in an X-linked recessive pattern.

• Definition: A genetic disorder caused by mutations in the gene coding for dystrophin, a protein essential for muscle fiber stability.

• Inheritance: X-linked recessive; primarily affects young males (ages 3-7).

• Pathophysiology: Absence or defect of dystrophin leads to unstable muscle cell membranes, resulting in muscle fiber damage and degeneration.

• Signs and Symptoms:

  • Gowers' sign: Characteristic way of rising from the floor using hands to 'walk up' the legs due to proximal muscle weakness.

  • Frequent falls

  • Difficulty getting up from lying or sitting position

  • Trouble running and jumping

  • Waddling gait

  • Enlarged calf muscles (pseudohypertrophy)

  • Muscle pain and stiffness

• Becker Muscular Dystrophy: A milder, later-onset version of Duchenne muscular dystrophy, also due to dystrophin gene mutations but with some functional protein present.

Example: A 5-year-old boy with frequent falls and difficulty rising from the floor is evaluated for DMD. Genetic testing confirms a dystrophin gene mutation.

The Motor Unit

Definition and Structure

A motor unit is the functional unit of neuromuscular control, consisting of a single somatic motor neuron and all the muscle fibers it innervates.

• Each motor neuron can contact multiple muscle fibers, but each muscle fiber is innervated by only one motor neuron.

• The site of contact is the neuromuscular junction (NMJ).

• The number of muscle fibers per motor unit varies widely and determines the precision of muscle control:

  • Small motor units (few fibers): fine control (e.g., eye muscles)

  • Large motor units (many fibers): gross movements (e.g., thigh muscles)

• Within a muscle, fibers of a single motor unit are distributed throughout the muscle, not clustered together.

Example: The hand muscles have many small motor units for precise movements, while the quadriceps have large motor units for powerful contractions.

Motor Unit Recruitment

Motor units are activated in a specific order to produce graded muscle contractions.

• Size Principle: Motor units with smaller, more excitable fibers are recruited first; larger units are recruited as more force is needed.

• Allows for smooth increases in muscle force.

Muscle Contraction Mechanics

Length-Tension Relationship

The force a muscle fiber can generate depends on its length at the time of stimulation, due to the degree of overlap between thick and thin filaments.

• Optimal Length (L0): The length at which maximal active tension is produced, typically near resting length.

• If the sarcomere is too stretched or compressed, fewer cross-bridges form, and tension decreases sharply.

• Most muscles operate within 70-130% of their resting length for optimal tension.

Equation:

Types of Muscle Contractions

• Isotonic Contraction: Muscle changes length while tension remains constant.

  • Concentric: Muscle shortens (e.g., lifting a weight).

  • Eccentric: Muscle lengthens (e.g., lowering a weight).

• Isometric Contraction: Muscle develops tension without changing length (e.g., holding a weight steady).

Example: During a biceps curl, lifting the dumbbell is concentric, lowering it is eccentric, and holding it steady is isometric.

Force-Velocity Relationship

There is an inverse relationship between the velocity of muscle shortening and the load (resistance) applied.

• As load increases, shortening velocity decreases.

• At maximal load, the muscle cannot shorten (isometric contraction).

Equation:

Muscle Twitch and Summation

Muscle Twitch

A muscle twitch is the response of a muscle fiber to a single action potential, consisting of three phases:

• Latent period: Time between stimulus and contraction onset.

• Contraction phase: Cross-bridge cycling and tension development.

• Relaxation phase: Ca2+ reuptake and tension decline.

Summation and Tetanus

• Wave (Temporal) Summation: Increased frequency of stimulation leads to greater tension as Ca2+ accumulates.

• Incomplete (Unfused) Tetanus: Partial relaxation between stimuli; tension fluctuates.

• Complete (Fused) Tetanus: No relaxation; maximal, sustained contraction.

Additional info: Tetanus ("lockjaw") is also a disease caused by Clostridium tetani toxin, leading to sustained muscle contraction.

Motor Unit Recruitment (Spatial Summation)

• Increasing the number of active motor units increases overall muscle tension.

• Small motor units are recruited first, followed by larger ones as needed (size principle).

Energetics of Muscle Contraction

ATP Sources and Metabolic Pathways

Muscle contraction requires large amounts of ATP, which is generated by several metabolic pathways:

• Creatine Phosphate (CP) System: Rapid transfer of phosphate from CP to ADP to form ATP; supports short bursts (first 15-30 seconds).

• Anaerobic Glycolysis: Glucose is converted to pyruvate and then lactate, yielding 2 ATP per glucose; does not require oxygen; supports short, intense activity.

• Aerobic Respiration: Complete oxidation of glucose (or fatty acids) in mitochondria; yields ~30-32 ATP per glucose; requires oxygen; supports prolonged activity.

Equation (Aerobic Respiration):

Oxygen Deficit and Recovery

• After exercise, extra oxygen is required to restore ATP, CP, and glycogen stores, and to convert lactate to glucose (Cori cycle).

• This increased oxygen consumption is called oxygen deficit or excess post-exercise oxygen consumption (EPOC).

Types of Skeletal Muscle Fibers

Classification by Contraction Speed and Metabolism

• Slow Oxidative (SO, Type I): Slow contraction, high myoglobin, many mitochondria, fatigue-resistant, rely on aerobic metabolism.

• Fast Oxidative (FO, Type IIa): Intermediate properties; both aerobic and anaerobic capacity.

• Fast Glycolytic (FG, Type IIb): Fast contraction, low myoglobin, few mitochondria, fatigue quickly, rely on anaerobic glycolysis.

Distribution: Muscles with more FG fibers appear pale; those with more SO fibers appear reddish. Most muscles are a mix, and fiber composition is genetically determined but can be modified by training.

Muscle Conditioning and Atrophy

• Hypertrophy: Increase in muscle size due to increased fiber size (not number).

• Atrophy: Decrease in muscle size due to disuse or denervation; can be reversible or, if severe, replaced by scar tissue (fibrosis).

Example: Weight training induces hypertrophy; immobilization in a cast leads to atrophy.

Smooth Muscle Microanatomy and Function

Structure and Specializations

Smooth muscle lines the walls of hollow organs and blood vessels. It is specialized for slow, sustained contractions and is controlled involuntarily.

• Spindle-shaped cells with a single central nucleus.

• No sarcomeres; filaments arranged in a meshwork, producing non-striated appearance.

• Dense bodies anchor actin filaments; contraction pulls on the cell membrane.

• Calmodulin (not troponin) is the regulatory protein for Ca2+-mediated contraction.

• Gap junctions allow coordinated contraction in single-unit smooth muscle.

Excitation-Contraction Coupling in Smooth Muscle

• Ca2+ enters from extracellular fluid via voltage-gated channels.

• Ca2+ binds to calmodulin, activating myosin light chain kinase (MLCK).

• MLCK phosphorylates myosin, enabling cross-bridge cycling and contraction.

Types of Smooth Muscle

• Single-unit (visceral) smooth muscle: Most common; cells connected by gap junctions; contract as a unit (e.g., intestines, uterus).

• Multi-unit smooth muscle: Fewer gap junctions; each cell contracts independently (e.g., large airways, arrector pili).

Muscle Disorders

• Necrotizing fasciitis: Rapidly spreading bacterial infection (e.g., Streptococcus), can destroy muscle tissue.

• Botulism: Caused by Clostridium botulinum toxin; blocks acetylcholine release, causing paralysis.

• Myasthenia gravis: Autoimmune disorder; antibodies destroy acetylcholine receptors, leading to muscle weakness.

• Poliomyelitis: Viral infection destroying motor neurons; prevented by vaccination.

• Hernia: Protrusion of a visceral organ through a muscular wall.