Muscle Structure and Fiber Types

Normal Muscle Structure

• Sarcomeres are defined as the region from one Z line to the next
• The I band contains only actin filaments
• The A band contains both myosin and actin filaments, overlapping each other
• The H band contains only myosin filaments
• The M line is where thick filaments attach

Types of Myofibers

• Type 1 muscle fibers, found in soleus and paraspinal muscles, are slow and red, with high levels of mitochondria, performing sustained contractions through oxidative phosphorylation, and are utilized in endurance training
• Type 2 muscle fibers, found in the triceps muscle, are fast and white, with low levels of mitochondria, quickly fatigue due to anaerobic glycolysis, and are utilized in weight/resistance training or sprinting

Normal Muscle Fiber Types

• Type I fibers have slow contraction velocity, are red, use oxidative phosphorylation for sustained contraction, have high myoglobin, and benefit from endurance training
• Type II fibers have fast contraction velocity, are white, use anaerobic glycolysis, and benefit from weight/resistance training and sprinting
• Adjacent motor units' fibers overlap and intermingle in a checkerboard pattern

Normal Muscle Sections

• In cross-sections skeletal muscle cells appear as large cells with peripheral nuclei
• Striations (numerous sarcomeres) can identify skeletal muscles in longitudinal sections

Muscle Contraction

• An action potential opens voltage-gated calcium channels on the presynaptic membrane (1)
• Acetylcholine (ACh) release triggers ACh receptors on the postsynaptic membrane, causing motor end plate depolarization that connects muscle cells helping to coordinate (2,3)
• Depolarization opens the dihydropyridine and ryanodine receptors which allows the sarcoplasmic reticulum to release calcium (4)
• Calcium binds to troponin to shift tropomyosin and expose the myosin-binding site on the actin filament (5,6)
• Myosin head binds to actin initiating the power stroke (7)
• Muscle shortening occurs by shortening the H and I bands between the Z lines, the A band stays the same length (7)
• ATP binding releases myosin from actin filaments, which returns to the cocked position (8,9)
• Calcium is resequestered in the sarcoplasmic reticulum (10)

Myogenic Injury

• Segmental myofiber degeneration and regeneration occurs when part of a myofiber undergoes necrosis
• Creatine kinase is released into the blood, and myophagocytosis occurs when macrophages remove damaged components of the myofiber during degeneration
• Regeneration begins with the fusion of an activated satellite cell to the damaged myofiber, and the regenerated fibers stain basophilic due to high levels of RNA
• Complete regeneration is not possible in a chronic disease process
• Myofiber hypertrophy is a physiologic response to exercise, though may be associated with disease
• Cytoplasmic inclusions from injury can include vacuoles, protein aggregates, and clustered organelles

Neurogenic Injuries

• Disruption of innervation of a muscle causes dysfunction in grouped atrophy
• The innervating motor neuron determines fiber type
• Denervation causes atrophy of fibers in a group, shown as a flattened, angular shape
• Reinnervation normalizes shape but may change fiber type
• Axons from nearby motor units extend to reinnervate myocytes, where newly reinnervated fibers become the fiber type of that motor unit
• Loss of checkerboard pattern results, and instead motor units appear as groups of myofibers of the same histochemical type, called fiber type grouping

Neurogenic vs Myopathic Injury

• Neurogenic atrophy is caused by affectations of motor neurons, causing atrophy of fibers as a group with a flattened, angular shape
• Myopathic disorders cause single fiber necrosis and regeneration, necrotic cells lose stain of nuclei with pale cytoplasm, shrink, and have irregular cell membranes, cytoplasm stains irregular with condensed areas
• Myopathic disorders show increased variability in fiber size, with hypertrophy or atrophy
• Regenerating myofibers in myopathic disorders show increased central nucleation, more basophilic H&E staining, hyperchromatic cytoplasm, and less hyperchromatic peripheral cytoplasm

Inherited Diseases of Skeletal Muscle

• Spinal Muscular Atrophy
• Muscular Dystrophy
• Myotonic Dystrophy
• Malignant Hyperthermia
• Congenital myopathies
• Diseases of Glycogen/Lipid Metabolism
• Mitochondrial Myopathies

Spinal Muscular Atrophy (SMA I)

• SMA I, also known as Werdnig-Hoffman disease, has childhood onset and progressive weakness
• SMA I is an autosomal recessive disease with a loss of function mutation in the SMN1 gene on chromosome 5, causing defects in spliceosomes impacting RNA splicing
• SMA I causes muscle weakness and atrophy due to loss of motor neuron innervation and degeneration of the anterior horns in the spinal cord
• Clinical features of SMA I include LMN signs, generalized hypotonia or floppy infant syndrome, presenting before 4 months of age, with death usually by 2-3 years
• Diagnostic feature include flattened, angulated, atrophic myofibers with normal and hypertrophied fibers and small groups retaining innervation

Muscular Dystrophies

• Progressive muscle weakness and wasting usually begin in early childhood
• Duchenne MD and Becker MD are the two most common muscular dystrophies
• Muscular dystrophies are X-linked, the gene is located in Xp21 responsible for encoding dystrophin

Duchenne Muscular Dystrophy (DMD)

• Duchenne is more severe and leads to death between ages 20-30
• Becker is milder in phenotype with a later onset
• Dystrophin is located in the plasma membrane over the Z band in order to strongly link with actin and connect the cytoskeleton with the ECM for mechanical stability
• Myocyte degeneration occurs when dystrophin is absent or abnormal, where myocyte damage occurring over time exceeds regenerative capacity
• DMD is X-linked recessive with a frameshift deletion or nonsense mutation of the dystrophin gene
• DMD results in absent dystrophin proteins and chronic muscle damage that cannot be contained by normal repair

DMD Histopathology

• Early disease presents as ongoing muscle damage with segmental myofiber degeneration and regeneration, an admixture of atrophic myofibers, myophagocytosis, and preserved fascicular architecture in muscle biopsies of young males
• As DMD progresses, muscle tissue is replaced by collagen and fat, causing pseudohypertrophy of calves, variations in myofiber size, and distorted fascicular architecture

DMD Presentation

• DMD is manifested by age 5 and walking may be delayed
• Weakness in pelvic girdle, extensions over shoulder muscles, and enlargement of calf muscles related to pseudohypertrophy are signs of DMD indicating muscle fiber increase due to fibroconnective tissue as muscle atrophies
• Life expectancy is 25-30 years

DMD Clinical Features

• Proximal muscle weakness and clumsiness characterize DMD
• Pseudohypertrophy enlarges calf muscles with associated muscle weakness and collagen and fat tissue replace muscle
• Patients affected by DMD use Gowers Sign to stand from sitting/lying positions
• Later symptoms of DMD are joint contractures, scoliosis, respiratory reserve decline, and sleep hypoventilation
• Patients with DMD may develop cardiomyopathy and arrhythmias because dystrophin is located in both skeletal muscles and the heart, and smaller amounts are also present in brain nerve cells
• Intellectual impairment and elevated serum creatine kinase are possible with DMD
• Respiratory insufficiency results in death between ages 20-30

Becker Muscular Dystrophy

• Becker is X-linked recessive, as well as a loss of function mutation of the dystrophin gene
• Results in a truncated, partially functional dystrophin protein
• Symptoms occur during adolescence or adulthood
• Characterized by less severe presentations of Duchenne MD at a more gradual rate
• Patients with Becker present symptoms later in life and maintain normal life expectancy
• Supports care manages Becker MD

Myotonic Dystrophy

• Myotonic dystrophy has an autosomal dominant inheritance pattern with CTG trinucleotide repeat expansions
• Age of onset spans from the 20s to 40s
• The length of expansion can correlate with disease severity
• Triplet expansions disrupt normal splicing
• A repeat expansion in the DMPK gene is responsible for encoding for myotonin-protein kinase
• The disruption of RNA splicing results in a deficiency of CLC1, a chloride channel normally involved in muscle relaxation, leading to myotonia

Myotonic Dystrophy Characterizations

• Myotonia characterizes abnormally slow relaxation of muscles and prolonged contractions
• Progressive muscle wasting and weakness is associated with type 1 fiber atrophy
• Grip myotonia, facial muscle weakness, frontal balding, cataracts, testicular atrophy, glucose intolerance, conduction defects in the heart, and increase serum CPK may be associated with muscular dystrophy as well

Ion Channel Myopathies

• Channelopathies are inherited mutations that impact the function of ion channel proteins
• Some channelopathies increase excitability and some decrease excitability
• Channelopathies are subclassified based on K levels examples are hyperkalemic, hypokalemic, or normokalemic
• Depending on the ion channel that is affected, manifestations include epilepsy, migraines, movement disorders with cerebellar dysfunction, peripheral nerve disease, and muscle disease

Ion Channel Myopathies: Mutations & Assoc. Diseases

• CACNA1S protein, a subunit of the muscle calcium channel, has a missense mutation that is the most common cause of hypokalemic paralysis
• CLC1 mutation affects chloride channels, and is associated with myotonia congenita, and decreased CLC1 expression in myotonic dystrophy
• Mutations in RYR1 disrupt the function of the ryanodine receptor that regulates calcium release from the sarcoplasmic reticulum. Results in congenital myopathy (central core disease) and malignant hyperthermia

Malignant Hyperthermia

• This life-threatening skeletal muscle channelopathy occurs due to autosomal dominant mutations in the voltage-gated RYR1 gene that impacts the Ryanodine receptor when controlling the Ca release from the Sarcoplasmic Reticulum
• Increased calcium release occurs with halogenated inhaled anesthetics and succinylcholine, which causes temporary paralysis with a rapid onset and short duration of muscle relaxation
• The interaction of anesthetic and mutant receptors cause increased calcium efflux and leads to tetany and heat production

Malignant Hyperthermia Clinical Features

• Characteristics of Malignant Hyperthermia include hyperthermia or hyperpyrexia, severe muscle contractions/tetany, tachycardia/tachypnea as a part of the Hypermetabolic state
• May occur from hereditary muscle diseases and congenital myopathies, dystrophies and metabolic myopathies
• Dantrolene (ryanodine receptor antagonist)

Congenital Myopathies: Central Core Disease

• An autosomal dominant mutation of the ryanodine receptor (RYR1) characterises Central Core Disease
• It presents with hypotonia at birth with skeletal abnormalities, and develop malignant hyperthermia
• Diagnosis includes, Biopsy: central/eccentric zones of disrupted sarcomere arrangement and areas of reduced oxidative and glycolytic enzymatic activity

Congenital Myopathies: Nemaline Myopathy

• Autosomal dominant/recessive mutations characterises Nemaline Myopathy
• NEM 1-7 gene mutations, involving thin filament of sarcomere and cause contractile dysfunction characterises Nemaline Myopathy
• Childhood weakness and floppy baby results in rods on the biopsy

Disorders of Lipid or Glycogen Metabolism

• General patterns include muscle dysfunction, either symptomatic from exercise/fasting from cramping to rhabdomyolysis, or slowly progressive muscle damage (non episodic)
• Examples include; Carnitine palmitoyltransferase II deficiency (Defect in free fatty acid transport into mitochondria), Myophosphorylase deficiency (McArdle disease) (Eg by myoglobinuria), Acid maltase deficiency (Pompe disease) (Impaired lysosomal conversion glycogen to glucose)

Carnitine Palmitoyltransferase II Deficiency

• It is a common lipid disorder that results from enzyme deficency
• Transport from free FFA into the mitochondira is impaired, resulting in toxic accumulation of FFA into the cytosol
• Episodes involve muscle damage from exercising or fasting that results in hypotonia, hypoglycemia and dilated cardiomyopathy

Diseases of Glycogen metabolism

• Myophosphorylase, skeletal muscle deficiency (Type V) results from ineffective breaking down of glycogen
• Epidoses damage exercising muscle, with painful cramps, as well as Myoglobinuria. There is also arrhythmia from electorlyte imbalances and normal normal blood glucose, with affects the liver
• Venous lactate-ammonia test are used to diagnosis, with lactate curve as the result, and elevated ammonia levels The treatment includes limits on diets high in carbs and careful exercise routines

Pompe Disease

• Acid maltase (lysosomal acid a-1,4-glucosidase) deficiency, type II affects the heart, liver, and muscle
• Impairs glycogen breaking down breakdown within lysosome which can result in cardiomegaly/hypertrophic cardiomyopathy, hypotonia, and exercise intolerance
• Enzyme replacement therapy is used to treat, as it has worked for patients with systemic symptoms early on

Mitochondrial Myopathies

• These are rare disorders and may involve many organ systems
• Causes mutation impairment of Mitochrondial DNA resulting in motherly inheritance because only oocyte factors into creating the mitochrondia to embryo
• All females affected has signs due to transmitted genetic code, and have affected males who cannot transit to children,
• The severity and effect is varitable depending on the ATP with high requirements, DRUG THERAPY FOR MERRF includes metabolic drug involving bettered celluar respiration like MERRF
• Weakness is variable but can still function, especially extraocular eye muscles, blurred eyes and inablily to move eyes are usually common

Mitochondrial Myopathies (MERRF)

• Myoclonic is the name this disease is called with MERRF, which is characterized by intermittent twitch from skeletal miscles, resulting in hicups, spasms, sleeping at irregular patterns,
• A biopsy needs to be done to diagonse, resulting ragged reds, serum cretinine kinase due to high increase amount of affected mitochrondia.
• Modified gomari trichrome stain is also used to visuilaize through staining. Leber is also characterized through this as well, and through vision changes, as well in males

Inflammatory Myopathies

• Immune-mediated inflammation causes injury, is a non-infectious inflammation to skeletal muscules resulting in weaknesses and myalgia
• Includes, Dermatomyositis, Polymyositis and Inclusion Body Myositis

Dermatomyositis

• Rare inflammation of skin and skeletal muscle results from Immune-mediated blood issues, peaking around 50-60
• Most common amongst females, which results from muscle cell damage, with gradual worsenings and can be life long
• Has a classic skin rash, Lilac coloring around eyes, which results in edema
• proximal muscels have also shown symmetric, and slow onset, which results in muscle myalgis, resulting in dysphagia
• Extramuscular involvement can cause around 10% of lung cases in interstitial issues as well
• Also can result in magilancy and cancer

Dermatomyositis: Autoimmune

• Pathology derives from smaller vessel damages in vascularity, with focus on immune issues and myocyte nacrosis.
• Genetics have been shown to come up, as well as increase in autoimmune diseases
• Associated issues includes; antihelecise which shows that, Anti-Mi2 Abs (anti-helicase) associated with Gottron papules

Dermatomyositis Diagnosis and Treatment

• Deposition and complement can cause major effect, causing capallliary bed to damage and inflame
• Increase cell creatin and reflect on blood
• Treatment is immunosupprespressants

Polymyositis

• Symmetric proximal muscle affects, where there is more skin involvement that affect people from ages 30 and 60 which is more commone in wommen. Affects heart, vessels and lungs with greater damage.
• This is caused by damages created during tissue dmg, where there are no more vascular issue History needs to be done to track the Endomysial where inflamation will be present of the cells, with muscles not doing their job
• Patient may show fatigue, with testing showing increase in cretaine

Dermatomyositis vs. Polymyositis

• Dermatomyositis is an antibody problem where immune drives perimysial with cell problems.
• Polymositis is the opposite-T cell drives this to affect mostly the cells themself

Inclusion-Body Myositis

• Inflammatory myopathy is the main problem, and very common within patients older than 65 yrs of age causing musucle weakness and slowly moving muscles
• Main involvement of muscle and dyspantha

Inclusion Body Myositis:

• Diagnostics from Labs show modorate elevated cells
• C1A or cytosolic can assist as well

Inflammatory Myopathies

• Dx tests are done through symptoms, but also through testing to determine nerve issues to create the findings
• High Ck serums and biopsies is recommended

Myasthenia Gravis and Lambert-Eaton Syndrome

• Myasthenia Gravis has defects and blocks ACh receptors, with Lambert Eaton it causes defect channels to block cell.

Myasthenia Gravis

• This is an autoimmune problem with causes lost of ACh receptors
• As auto-Abs and Acetyl receptors is damages in synape, destruction the fibers which creates less response. Complement factors leads to problems.

Myasthenia Gravis: Key Traits

• Commonly are bimodal to have equal females and males which affects both in equal terms from 20 to 70 age
• painless with increase exercise, and proximal muscles affected more with diapragham. Muscle issues increase as with exercise
• Diplopia and ptosis with swallowing issues as the result
• Testing for electro and normal cordudaction can assist with the problems as well
• acetyl can treat the muscles as well

Lambert Eaton Myasthenic Syndrome

• Rare autoimmune which affects males more, with age spikes coming up, as autoantibody damages cell from producing Calcium so muscles are restricted to respond
• Clinical muscle weakness show improvements during the exercise
• Autonomic issues including consipation and dry mouth
• 50% have cardio issues
• Tested through e-diagnostics
• Injected treatment to provide more ACH