Skeletal Muscle Disorders

Key Terms

Atrophy → decrease in muscle fibre size.

Hypertrophy → increase in muscle fibre size.

Sarcopenia → age-related loss of muscle mass.

Cachexia → severe muscle/fat wasting caused by chronic disease.

Muscular dystrophy → inherited disorders causing progressive muscle fibre damage/loss.

Satellite cell → muscle stem cell involved in repair and regeneration.

Eccentric contraction → muscle produces force while lengthening.

Sarcomere → basic contractile unit of muscle.

Dystrophin → protein that helps stabilise the muscle fibre membrane.

CK → enzyme released into blood when muscle is damaged.

Proximal → closer to the body's centre.

Distal → further from the body's centre.

Myotonia → delayed muscle relaxation after contraction.

Fasciculation → involuntary muscle twitch.

Spasticity → abnormal increased muscle stiffness/tone associated with UMN damage.

Cardiomyopathy → disease of the heart muscle.

Cytokine → signalling protein involved in communication/inflammation.

Anabolic → promoting tissue growth/building.

Fibrosis → formation/accumulation of scar tissue.

Orthosis → supportive device used to help control/support a body part.

Gene therapy → treatment that aims to alter or replace genetic material.

Eccentric exercise - the muscle is producing force while it is lengthening


Skeletal Muscle Structure

Micronuclei - On the perimeter of healthy muscle fibres




Structure

  • Have 2 ends, usually attached to bones via tendons

  • Epimysium - connective tissue surrounding each muscle

  • Fascicles - organised by Epimysium forming bundles of muscle cells

  • Perimysium - connective tissue that separates individual fascicles

  • Myofiber - Individual muscle cells

  • Endomysium - connective tissue surrounding connective tissue

  • 3 connective tissues bind muscle cells together and are continuous with tendons


Features of skeletal muscle cells

  • Sarcolemma - plasma membrane of skeletal muscle

  • T-Tubule - invagination of sarcolemma, that extents deep into muscle fibre

  • Sarcoplasmic reticulum - ER of muscles, surrounds each myofibril, ends near T-tubule region called terminal cisternae

  • Triad - Region where 1 T-Tubule is flanked by 2 terminal cisternae

  • Myofibril - Bundle of contractile filaments within muscle fibre

  • Nucleus, mitochondria, cytosol.



Organisation of a Myofibril

  • Actin - thin filament

  • Myosin - thick filament

  • A Band - Quite dark, length of thick filaments

  • I Band - very light region - with thin but no thick filaments

    • length decreases during contraction.

  • Z line - bisects I band. protein disc onto which thin filaments attach

  • H zone - region where only thick filaments present. length decreases during contraction

  • M line - Middle of A band. Region where thick filament attach.

  • Sarcomere - unit of contraction - region between 2 Z lines


Sliding Filament Theory

Components

  • ATP

  • Ca2+

  • Myosin

  • Actin

  • Tropomyosin

  • Troponin


Myosin

  • thick filaments

  • Globular head and long tail

  • Tails or 2 myosin’s wind each other

  • ATP binds at low energy state

  • ATP hydrolysed to ADP + P1

  • energy transferred to myosin - high energy state


Process

  1. Thin filaments made of Actin, Tropomyosin and Troponin.

  2. Major component is Actin. Filament organisation-two chains composed of actin monomers wound around each other.

  3. Each Actin monomer has single Myosin binding site (MBS) on external surface.

  4. MBS on Actin is normally covered by the protein Tropomyosin.

  5. Troponin found on thin filaments.

  6. Ca2+ binds Troponin which moves Tropomyosin off the MBS on the Actin molecules.


Muscle fibre types

Slow twitch (type I) - red

small motor unit innervation, smaller, easily excitable, aerobic, high capillary density, high myoglobin, many mitochondria, highly fatigue resistant

Fast twitch (type II) - white

  • Type IIX/IIB

large motor unit innervation, relatively unexcitable, high glycogen, low myoglobin, extensive sarcoplasmic reticulum, highly glycolytic, low fatigue resistance

  • Type IIA

intermediate properties but aerobic with high myoglobin


Muscle Plasticity

Muscle plasticity - the ability of skeletal muscle to change its structure and function in response to different demands


Cross-innervation

Different types of muscle fibres can change their characteristics depending on the type of motor neuron supplying them.


  • Slow-twitch (Type I) fibres → suited to prolonged, aerobic activity and are fatigue-resistant.

  • Fast-twitch (Type II) fibres → suited to producing high force but fatigue more quickly.


The nervous system therefore plays an important role in determining muscle fibre characteristics.


Training

High repetition + low force

  • Associated with adaptations useful for endurance.

Increases/maintains features such as:

  • Mitochondria

  • Capillaries

  • Fatigue resistance


Low repetition + high force

  • Produces adaptations associated with strength.

  • Increases fibre cross-sectional area (CSA) and strength.

CSA = cross-sectional area
→ essentially the size of the muscle fibre when viewed in cross-section.


Muscle Damage and Repair

Eccentric exercise - the muscle is producing force while it is lengthening


  • Lifting the bag up → your bicep shortens while working = concentric contraction.

  • Lowering the bag slowly → your bicep is still working, but it gets longer as the bag comes down = eccentric contraction.


Eccentric contractions can create tiny microscopic tears in muscle fibers and the surrounding connective tissue.


Satellite cells - muscle stem cells located around muscle fibres that help with muscle growth and repair.



After muscle damage:

  1. Muscle fibres are damaged.

  2. Immune cells enter the damaged area.

  3. Satellite cells become activated.

  4. They contribute to repair/regeneration of muscle fibres.

  5. Newly regenerated fibres can initially have centrally located nuclei.


  • Healthy mature skeletal muscle fibres normally have their nuclei towards the periphery, so centrally nucleated fibres can be a sign of regeneration after damage.


Muscle loss

Muscle loss occurs in many conditions, including:


  • Metabolic diseases

    • Type II diabetes

    • Alcoholic liver disease

    • COSarcopenia = loss of muscle mass during ageing.PD

  • Ageing

  • Cancer

  • Muscular dystrophy

  • Muscular atrophy


Muscle atrophy

Atrophy - reduction in the size of muscle fibres.

This is different from muscle loss caused by destruction of muscle fibres


Muscular dystrophy

Muscular dystrophy is a group of inherited genetic disorders characterized by progressive muscle weakness and muscle wasting due to degeneration of muscle fibers.


Sarcopenia

Sarcopenia - loss of muscle mass during ageing.


  • Approximately 50% muscle loss between ages 50–90.

  • Loss of muscle power.

  • Reduced mobility.

  • Increased risk of falling.


Causes

  1. Motor neuron loss

  • Motor neuron death mainly affects fast-twitch motor units.

  • This causes fast-twitch fibre atrophy.

  • Remaining fibres can become re-innervated by slow-twitch motor neurons.


2. Reduced response to anabolic stimuli

Anabolic = promoting growth/building of tissue.

The ageing muscle has a reduced response to:

  • Amino acids

  • Insulin

  • Resistance training


3. Satellite cell changes

  • Satellite cells become less responsive.

  • They may have a reduced ability to self-renew.

  • There may be reduced expression of growth factors.



4. Reduced force production

Even an individual muscle fibre may produce less force.

Possible reasons include:

  • Fewer cross-bridges

  • Oxidation of the ryanodine receptor


Ryanodine receptor = a protein involved in releasing calcium from the sarcoplasmic reticulum, which is essential for muscle contraction.


Disuse and immobilisation

Muscle mass and strength can be lost through muscle fibre atrophy during:

  • Spinal cord lesions

  • Immobilisation after a bone fracture

  • Long-term space flight

  • Long-term bed rest


Sarcomere loss

A reduction in the number of sarcomeres in series can occur with:

  • Cerebral palsy/spasticity

  • Walking on high heels

  • Immobilisation after a bone fracture


Cachexia

Cachexia = severe wasting of the body, particularly muscle and fat, caused by chronic illness


Examples include:

  • Cancer

  • AIDS

  • COPD

  • Renal failure


Cancer cachexia

  • It can affect up to 80% of patients with advanced cancer.

  • Around 30% body-weight loss is a strong predictor of death.

  • It contributes to around 30% of cancer-related deaths.

  • Wasting of the respiratory muscles can contribute to death.

  • It is not reversed by conventional nutritional support.


Possible mechanism

Tumour/inflammatory cells release cytokines.

Cytokines = signalling proteins released by cells that can influence inflammation and other cellular processes.

These cytokines can:

→ increase muscle protein degradation
→ cause muscle wasting
→ impair satellite-cell function


Myostatin

Myostatin (MSTN) - a protein that normally limits muscle growth.


Animals/humans with reduced myostatin activity can have:

  • Increased muscle mass

  • Reduced adipogenesis


Adipogenesis = formation of fat cells.


Therefore, inhibiting myostatin was considered as a possible treatment strategy for:

  • Muscular dystrophy

  • Muscle atrophy

  • Metabolic conditions

  • Cachexia

  • Sarcopenia


Activin receptor type 2 inhibition

The idea is to interfere with signalling from:

  • Myostatin

  • Activin

This could potentially reduce signals that inhibit muscle growth.


Duchenne muscular dystrophy — DMD

Pathology

DMD involves:

  • Progressive loss of muscle fibres

  • Replacement of muscle with:

    • Fat

    • Scar tissue

  • Progressive decline in muscle function


DMD is caused by:

  • Mutations in the dystrophin gene

  • X-linked recessive inheritance


X-linked recessive - the disease-causing gene is on the X chromosome and typically affects males much more frequently.


Epidemiology

  • Approximately 1 in 3,500 live male births.

  • High spontaneous mutation rate.

  • Death typically occurs in the 20s or early 30s according to the lecture.


Diagnosis

  • Clinical history

  • Creatine kinase (CK) levels

  • Genetic testing

  • Muscle biopsy


CK = creatine kinase, an enzyme released into the blood when muscle fibres are damaged.


DMD treatment

Current conventional therapies listed in the lecture include:

  • Steroids

  • Surgery

  • Ventilation

  • Heart drugs:

    • ACE inhibitors

    • Beta-blockers

  • Physiotherapy


Glucocorticoid steroids

These are used chronically in DMD.

The lecture states that they can:

  • Increase strength

  • Prolong ambulation

  • Delay loss of ambulation

  • Reduce the need for spinal fusion

Treatment is generally initiated around 4–6 years


Side effects can include:

  • Behavioural changes

  • Weight gain

  • Impaired glucose tolerance

  • Growth suppression

  • Excessive hair growth

  • Adrenal suppression

  • Muscle loss

Dystrophin

Dystrophin - an important protein that helps stabilise the muscle fibre membrane during contraction.


Why is dystrophin important?

Muscle fibres experience mechanical stress every time they contract.

  • Dystrophin helps the membrane withstand this stress.



Without functional dystrophin:

→ membrane becomes more vulnerable to damage
→ muscle fibres become damaged
→ fibres progressively degenerate
→ muscle is replaced by fat/scar tissue
→ weakness develops.


Limb-girdle muscular dystrophy — LGMD

Limb-girdle muscular dystrophy (LGMD) - a group of muscular dystrophies characterised particularly by weakness around the hips and shoulders.


  • Many different gene mutations can cause LGMD.

  • There are both dominant and recessive forms.



Prevalence : approximately 20–40 per million.

  • Can begin in childhood or adulthood.

  • Causes proximal muscle weakness.

  • May involve cardiomyopathy.

  • Some patients may become wheelchair-dependent.

  • Life expectancy may be reduced.


Proximal = closer to the centre of the body, e.g. shoulder and hip muscles.


Diagnosis

  • History

  • CK levels

  • Genetic testing

  • Biopsy


Management includes:

  • Heart monitoring

  • Respiratory care

  • Physiotherapy

  • Mobility aids


Facioscapulohumeral muscular dystrophy — FSHD

Facioscapulohumeral muscular dystrophy (FSHD) - a muscular dystrophy particularly affecting the face and shoulder muscles.



Key facts

  • Mutation involving a region of chromosome 4

  • Associated with abnormal DUX4 expression

  • Autosomal dominant inheritance

  • Prevalence approximately 1:15,000

  • Usually begins before age 20

  • Facial and shoulder muscle weakness

  • Around 20% wheelchair dependent according to the lecture


Diagnosis

  • Clinical history

  • CK levels

  • Genetic testing

  • Sometimes biopsy


Management includes:

  • NSAIDs

  • Possible surgery to stabilise shoulder blades

  • Physiotherapy

  • Orthoses


Orthosis = a device used to support or control part of the body, e.g. an ankle/foot support.


Myotonic dystrophy

Myotonic dystrophy - an inherited muscle disorder involving muscle weakness and myotonia.

Myotonia - delayed relaxation of a muscle after it contracts.


There are two main forms discussed:

  • DM1

  • DM2


Cause

Both involve an abnormal gene expansion.

This causes misregulation of RNA splicing.


Clinical features

  • Weakness of distal muscles

  • Respiratory muscle weakness

  • Myotonia


Nemaline myopathy

Nemaline myopathy = a muscle disorder involving abnormal proteins associated with the muscle's thin filaments.


Cause

Mutations in genes encoding small filament-associated proteins, including:

  • Nebulin

  • Skeletal α-actin


Features

  • Usually early onset

  • General muscle weakness

  • Particularly affects respiratory muscles

  • Normal CK levels


Motor neurone disease — MND

Although MND is primarily a neurodegenerative disease, it causes major muscle pathology because the neurons controlling muscle movement degenerate.


Motor neurons

Upper motor neurons (UMNs)

  • Originate in the brain/cortex.

  • Their degeneration is associated with spasticity.

Lower motor neurons (LMNs)

  • Originate in the spinal cord.

  • Their degeneration causes:

    • Muscle wasting

    • Weakness


Overall idea

Motor neurons act as the communication system between the brain and muscles.


In MND:

Motor neuron degeneration → loss of communication with muscle → weakness + wasting.



Amyotrophic lateral sclerosis — ALS

ALS = amyotrophic lateral sclerosis, a form of motor neurone disease.


Epidemiology

  • Incidence: approximately 2 per 100,000

  • Slightly more common in males

  • Peak age of onset: 6th decade

  • Age range can be approximately 20–90

  • Around 95% are sporadic

Sporadic = occurring without an obvious inherited/familial cause.


Symptoms

  • Loss of muscle strength

  • Muscle atrophy

  • Fasciculations — involuntary muscle twitches

  • Muscle cramps

  • Slowed movements

  • Loss of dexterity

Dexterity = ability to perform precise, coordinated movements.


Viral gene delivery

One approach is using adeno-associated virus (AAV).

AAV = adeno-associated virus, a virus used as a vehicle to deliver genetic material.

Advantages:

  • Non-pathogenic in humans

  • Very efficient gene transfer

Problem:

  • AAV has a DNA carrying capacity of about 4,000 base pairs (bp).

  • Dystrophin is approximately 12,000 bp.

Therefore, the complete dystrophin gene is too large to fit easily into AAV.

Gene delivery can be:

  • Intramuscular

  • Intravascular



Summery