ToB 7.2 Muscle Disorders

Muscle Repair

• Skeletal Muscle Cells

  • Cannot divide, but can regenerate by the action of Satellite cells.
  • Skeletal muscle cells are mononucleated quiescent cells (myofibres) with resident stem cells (satellite/pstem cells).

• Satellite Cells and Regeneration (Skeletal Muscle)

  • In response to injury, satellite cells divide and differentiate into new myotubes.
  • These new myotubes fuse with existing myofibres, leading to an increase in muscle mass (hypertrophy).
  • This regenerative capacity underpins skeletal muscle repair but is limited by age and extent of injury.

• Cardiac Muscle Cells

  • Incapable of true regeneration after injury.
  • Fibroblasts invade and divide to lay down scar tissue, leading to fibrotic replacement rather than true regeneration.

• Smooth Muscle Cells

  • Retain mitotic activity and can form new smooth muscle cells.
  • Example: in a pregnant uterus by hypertrophy (swelling) and hyperplasia (increase in cell number).
  • Muscle wall thickening can occur via size increase and/or cell number increase.

Muscle Remodelling

• Skeletal Muscle Remodelling Overview

  • Contractile proteins (actin and myosin) are replaced approximately every two weeks. ext{replacement cycle}
    oughly = 2 ext{ weeks}.
  • Replacement balance determines outcome:
  • Atrophy when destruction exceeds replacement.
  • Hypertrophy when replacement exceeds destruction.
  • Remodelling is driven by myokines (cytokines released by muscle) that exert systemic effects.
  • Hypertrophy is associated with increased mitochondrial content in skeletal muscle.
  • Exercise stimulates remodelling; Laurens et al., 2020 cited for skeletal muscle remodelling effects.

• Atrophy and Its Types

  • Atrophy results from reduced muscle activity or loss of nerve input:
  • Disuse Atrophy (Skeletal Muscle Remodelling): due to physical inactivity or immobilisation.
  • Sarcopaenia: age-related muscle loss.
  • Denervation Atrophy: due to damage to nerves supplying the muscle.
  • Denervation atrophy exemplified by tongue atrophy after hypoglossal (CN XII) injury.

• Evidence of Disuse Atrophy

  • Soleus muscle biopsy after 30 days of bed rest shows Z-line streaming indicating muscle damage.
  • Sedentary behaviour or immobilisation leads to reduced fibre diameter and loss of power.

• Age-Related Muscle Loss

  • By age 80, around $50 ext{ extpercent}$ of muscle mass can be lost; resistance training can counteract this decline.
  • MRI data show muscle mass decline from age 30; comparisons between 25-year-old and 75-year-old individuals illustrate sarcopaenia.
  • Visualization: mid-thigh MRI comparing a 25-year-old healthy adult to a 75-year-old healthy adult.

• Effects of Denervation and Nerve Supply

  • Disrupted nerve supply to muscle leads to weakness and atrophy (denervation atrophy).
  • Denervation also affects muscle fibres like the tongue following hypoglossal nerve injury.

• Neural Regeneration (PNS) Overview

  • If cell bodies remain intact, severed peripheral nerves can regenerate.
  • Process:
  • Injury leads to degeneration of distal axon segments.
  • Macrophages release growth factors.
  • Proliferating Schwann cells guide axon regrowth.
  • Regeneration starts from the proximal axon and is supported by Schwann cells.
  • Once the neuromuscular junction (NMJ) is re-established, muscle function is restored.
  • Peripheral nervous system capable of regeneration under suitable conditions.

Myasthenia Gravis

• Overview

  • Epidemiology: Most common in women under 40 and men over 60; population data from Ireland and UK show notable incidence; prevalence around 100,000 in the UK.
  • Clinical features: Fatigability; ptosis; diplopia; blurred vision; dysarthria; dysphagia; dyspnea; symptoms worsen with stress or fatigue; variable severity.
  • Pathophysiology: Autoimmune disorder targeting the neuromuscular junction.
  • Investigations and etiology: Involves autoantibodies that disrupt NMJ transmission; genetic and environmental factors contribute to disease expression.
  • Management: Avoid triggers; acetylcholinesterase inhibitors (e.g., neostigmine, pyridostigmine); thymus management (thymectomy) due to thymic involvement.

• Pathophysiology in NMJ

  • Antibodies block/destroy nicotinic ACh receptors at the NMJ.
  • Causes loss of junctional folds and widening of the synaptic cleft.
  • Result: Reduced muscle contraction due to impaired ACh receptor function.
  • NMJ in MG shows normal ACh receptors overall but with blockade by anti-ACh antibodies and structural changes at the synapse.

• Clinical Features and Symptoms

  • Fatigability is a hallmark; severity varies with stress and tiredness.
  • Ptosis and blurred vision are common early signs.
  • Other features: proximal weakness, diplopia, dysarthria, dysphagia, dyspnea in severe cases.

• Investigations and Epidemiology

  • Population-based data indicate MG is more common in certain age and gender groups (e.g., women
  • Incidence data include international references (Ireland and UK summaries) with age-at-onset distribution.

• Management Details

  • Avoid triggers that worsen fatigue and cholinergic symptoms.
  • Acetylcholinesterase inhibitors increase ACh availability at the NMJ to improve contraction.
  • Thymus removal (thymectomy) is considered due to thymic abnormalities in MG.

• Organophosphate Poisoning and Botulism (NMJ Disruption in Other Contexts)

  • Botulism: Inhibits release of acetylcholine (ACh) at the NMJ, leading to flaccid paralysis.
  • Organophosphate poisoning: Irreversibly inhibits acetylcholinesterase, causing excess ACh at the NMJ and widespread cholinergic symptoms; can produce excessive sweating, lacrimation, blurred vision, seizures, agitation, respiratory arrest, and other neurotoxic symptoms.
  • Organophosphates are used as pesticides or chemical weapons; the result is impaired breakdown of ACh at the NMJ.

Muscular Dystrophies

• Overview

  • Genetic disorders leading to progressive muscle wasting and weakness.
  • Major types include Duchenne and Becker (DMD/BMD); Emery-Dreifuss; Limb Girdle MD (LGMD); Fascio-Scapulo-Humeral MD; Distal MD; Oculopharyngeal MD.

• Duchenne and Becker Muscular Dystrophies (DMD/BMD)

  • Pathophysiology
  • Dystrophin gene mutation on X chromosome (X-linked recessive).
  • Dystrophin glycoprotein complex connects the cytoskeleton to the basal lamina; its disruption weakens the sarcolemma during muscle contraction.
  • Dystrophin is a key membrane-associated protein; the dystrophin-glycoprotein complex includes dystroglycans, sarcoglycans, and other components that stabilize the muscle fiber membrane.
  • Inheritance
  • X-linked recessive: affected males; carrier females.
  • Typical pattern: affected males pass the mutation to all daughters (as carriers) but none of their sons; affected males produce carrier daughters and affected sons when mated with carriers.
  • Carrier females can transmit the mutation to half of their sons (affected) and half of their daughters (carriers).
  • 10% of female carriers may show some manifestations.
  • Dystrophin Gene Mutations
  • Duchenne: nonsense or frameshift mutations leading to no dystrophin production; earlier and more severe
  • Becker: missense (in-frame) mutations leading to reduced or truncated dystrophin; milder, later-onset disease
  • Histopathology and Staining
  • Duchenne: absence of dystrophin; histology shows increased fat and connective tissue and myofiber degeneration; dystrophin staining is absent or greatly reduced in affected muscles.
  • Clinical Features and Progression
  • Typical onset in early childhood; progressive proximal muscle weakness.
  • Gowers’ sign: using hands to push off thighs to achieve standing from a squat due to proximal weakness.
  • Calf pseudohypertrophy due to replacement of muscle with fat and connective tissue.
  • Early difficulty with stairs, running, and climbing; frequent falls; scoliosis; respiratory involvement over time.
  • Epidemiology
  • Incidence about $\frac{1}{3500}-\frac{1}{5000}$ male births; life expectancy historically into early adulthood; median life expectancy improving with care.
  • Case and Typical Course
  • Case study example: early proximal weakness; elevated CK levels (see CK values below); absent dystrophin; DMD diagnosis.

• Becker Muscular Dystrophy (BMD)

  • Generally milder and later onset than DMD; dystrophin is present but reduced or abnormal.

• Other Related Dystrophies

  • Limb Girdle MD (LGMD): dystrophin glycoprotein complex components or related proteins; predominantly affects shoulder and hip girdles.
  • Distal and Oculopharyngeal MD: distinct clinical patterns with distal muscle weakness or palatal/opharyngeal involvement.

• Dystrophin-Glycoprotein Complex and Related Proteins

  • Dystrophin connects intracellular cytoskeleton to the extracellular matrix via the dystrophin-glycoprotein complex (including dystrophin, dystrobrevin, sarcoglycans, dystroglycans, sarcospan, and others).
  • Loss or dysfunction of this complex destabilizes the sarcolemma during contraction.

• Histology and Diagnosis

  • Muscles may show variability in fiber size, central nuclei, fatty infiltration, and connective tissue deposition.
  • Immunostaining for dystrophin shows absence in DMD and reduced/broken staining in BMD.
  • Serum creatine kinase (CK) is markedly elevated in affected boys.

• Case Study: Duchenne Muscular Dystrophy (DMD)

  • Presentation: progressive proximal weakness of the lower limbs starting around age 4, followed by upper limbs.
  • Early indicators: unable to walk without support by age 9; total wheelchair dependence by age 12; scoliosis from age 12.
  • Laboratory: creatine kinase (CK) markedly elevated; example value: $ext{CK} = 2600 ext{ IU/L} ext{ (normal }50-150 ext{ IU/L)}$.
  • Genetic/Protein finding: absence of dystrophin protein.
  • Diagnosis: Duchenne Muscular Dystrophy (DMD).

Malignant Hyperthermia

• Genetic Susceptibility and Aetiology

  • Susceptibility approximately $1/10000$; genetic predisposition due to a mutation, most commonly autosomal dominant in the RYR1 gene.

• Pathophysiology

  • Exposure to triggering agents (anesthetics) causes excessive Ca²⁺ release from the sarcoplasmic reticulum in skeletal muscle.
  • Results in a hypermetabolic state with increased heat production and muscle rigidity.
  • Calcium release leads to increased oxygen consumption and CO₂ production, contributing to metabolic acidosis.

• Clinical Features

  • Muscular rigidity, hypercapnia, hypoxaemia, rhabdomyolysis, hyperkalemia, extreme hyperthermia, acidosis, and potential fatal outcomes if not treated promptly.

• Management (Clinical note, not shown in slides but standard practice)

  • Immediate dantrolene administration, avoidance of triggering anesthetics, aggressive cooling, and supportive care.

Rhabdomyolysis

• Definition and Consequences

  • Rapid breakdown of skeletal muscle tissue with release of intracellular contents (e.g., myoglobin) into the circulation.
  • Can cause kidney damage following trauma, drug use, excessive exercise, or statin use.
  • Incidence cited: $1/100{,}000$.

• Clinical Relevance

  • Myoglobinuria can lead to acute kidney injury; clinical suspicion warranted in severe muscle breakdown with dark urine and rising CK.

Key Terms (from the transcript)

• Myopathy: Primary disease of muscle.
• Sarcopaenia: Wasting as a result of ageing.
• Hypertrophy: Enlargement of an organ or tissue due to an increase in the size of its cells.
• Dystrophy: Degeneration of tissue due to disease (genetic).
• Atrophy: Wasting due to underuse.
• Hyperplasia: Enlargement of an organ or tissue from the increase in the number of its cells (due to increased reproduction rate of cells).

Supplementary Notes and Connections

• Learning outcomes alignment

  • Understand limited repair capacity in mature skeletal and cardiac muscle.
  • Describe skeletal muscle remodeling and its relevance to atrophy and hypertrophy.
  • Explain pathophysiology and clinical features of myasthenia gravis.
  • Explain disruption of neuromuscular transmission in botulism and organophosphate poisoning.
  • Explain pathophysiology of Duchenne muscular dystrophy and malignant hyperthermia.

• Connections to foundational principles

  • Principle of tissue regeneration limits in postnatal tissues (skeletal vs cardiac).
  • Balance of anabolic and catabolic processes governs muscle mass (remodelling).
  • Neuro-muscular junction integrity is critical for motor function; autoimmunity or toxins can disrupt transmission.
  • Genetic disorders of structural proteins (dystrophin) have downstream membrane integrity and signaling consequences.

• Ethical, philosophical, and practical implications

  • Genetic testing and carrier screening for X-linked dystrophinopathies raise ethical questions about family planning and disclosure.
  • Management of chronic dystrophy conditions involves multidisciplinary care, quality of life considerations, and accessibility to supportive therapies.

• Formulas and numerical references (LaTeX)

  • CK level example: $ext{CK} = 2600 ext{ IU/L} \ ( ext{normal }50-150 ext{ IU/L})$
  • Incidence data: Duchenne/Becker distribution context: $1/3500 ext{ to } 1/5000$ male births.
  • Dystrophin-related carrier expectations (inheritance): X-linked recessive patterns with carrier daughters and affected sons; more formal expression would be: if an affected male (X^d Y) mates with a carrier female (X^D X^d), offspring proportions follow Mendelian inheritance with daughters: 50% X^D X^d (carriers) and 50% X^d X^d (affected); sons: 50% X^D Y (unaffected) and 50% X^d Y (affected). The slide summarizes the rule: “on average 50% of their daughters will be homozygous and affected and 50% will be heterozygous and carriers,” and “no male-to-male transmission.”
  • Organophosphate susceptibility: $\frac{1}{10000}$.
  • Age-related muscle loss: $50 ext{ extpercent}$ by age 80.
  • UK prevalence reference: $ext{approximately }10^5 ext{ people}$.