anatomy
poorva
MusclePathophysiology-2.pptxMuscle Pathophysiology
Srujana Rayalam DVM, PhD
Dept. of Pharmaceutical Sciences
PCOM-GA campus
PHAR 113G Anatomy, Physiology & Pathophysiology I
8/24/2020 6:18 PM
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Learning Objectives
Define a motor unit, describe the general types of peripheral nerve injury and contrast denervation atrophy vs. myopathy.
Describe the characteristics of the two muscle fiber types.
Describe the neuropathies caused by infectious pathogens - Guillain-Barre syndrome and chickenpox.
Describe the metabolic and nutritional neuropathy caused by diabetes mellitus.
Describe traumatic neuropathies - compression neuropathy.
Describe the pathophysiology of motor neuron disease, X-linked muscular dystrophies.
Describe channelopathies and explain how alcohol, statins, steroids and chloroquine can cause myopathy.
Explain the pathophysiology of myasthenia gravis and differentiate it from Lambert-Eaton myasthenic syndrome.
Neuromuscular Diseases
Complex group of disorders with numerous inherited and acquired causes
typically present with weakness, muscle pain, or sensory deficits
Classification of neuromuscular diseases
Spinal muscular atrophy and disorders associated with motor neurons
Disorders of peripheral nerves
Disorders of skeletal muscles
Disorders of neuromuscular junction
Motor Unit
Motor unit includes one alpha motor neuron and all the muscle fibers that it innervates.
Cell bodies are present in anterior horn; larger the cell body, higher the conduction velocity.
The number of fibers innervated by a single motor neuron varies (from a few to thousand).
The fewer the number of fibers per neuron the finer the movement.
Major components of a neuron
Amyotrophic Lateral Sclerosis
Mixed upper and lower motor neuron deficits
Affecting limb and bulbar muscles
Involvement of bulbar muscles causes difficulty with swallowing, chewing, speaking, breathing, and coughing.
Progressive and generally fatal within 3–5 years (pulmonary infection and respiratory failure)
Segment of spinal cord viewed from anterior (upper) and posterior (lower) surfaces showing attenuation of anterior (motor) roots compared to posterior (sensory) roots.
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Motor Neuron Disease (Lou Gehrig’s disease)
The ALS Ice Bucket Challenge
Since July 29, 2014, The ALS Association has received more than $115 million in donations!
ALS (Lou Gehrig Disease)…cont’d
Pathogenesis:
Missense mutation in copper-zinc superoxide dismutase (SOD1) gene
Toxicity mediated by increased levels of the neurotransmitter glutamate
Neurofilamentous inclusions in cell bodies and proximal axons
Lou Gehrig at Yankee Stadium in 1939, his final season with the Bombers.
Diseases of Peripheral Nerves
Inflammatory Neuropathies
Infectious Polyneuropathies
Diptheria
Leprosy
Varicella – Zoster Virus
Acquired Metabolic and Toxic Neuropathies
Diabetes mellitus
Thiamine deficiency
Alcohol consumption
Traumatic Neuropathies
Compression Neuropathy
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Axonal degeneration and muscle fiber atrophy
Primary destruction of the axon, with secondary disintegration of its myelin sheath.
Causes: trauma, abnormal cell body (neuronopathy) or axon (axonopathy)
Pathology: the axon and its myelin sheath undergo degeneration, with resulting denervation atrophy of the myocytes → breakdown of myosin and actin → ↓ cell size, but myocytes remain viable.
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Nerve regeneration and reinnervation of muscle
Sprouting of adjacent (red) uninjured motor axons leads to fiber type grouping of myocytes, while the injured axon attempts axonal sprouting.
e.g., recovery of muscle contraction in poliomyelitis
Exercise rehabilitation
Electrical stimulation
Stem cell transplant
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Denervation Atrophy vs. Myopathy
Myopathy: Scattered myocytes of adjacent motor units are small whereas the neurons and nerve fibers are normal.
e.g., Type II fiber atrophy with sparing of type I fibers is seen with prolonged corticosteroid therapy or disuse.
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Denervation atrophy: Atrophy of myocytes due to axonal degeneration
Reinnervation can correct denervation atrophy
Inflammatory Neuropathies
Characterized by inflammatory cell infiltrates in peripheral nerves, roots, and sensory and autonomic ganglia
Guillain-Barré Syndrome
Immune-mediated demyelinating neuropathy
Life threatening disease
Ascending paralysis
Pathogenesis:
acute, influenza-like illness
bacterial and viral infections
T-cell mediated immune response
segmental demyelination induced by activated macrophages
The nerve conduction velocity is slowed because of the multifocal destruction of myelin segments involving many axons within a nerve
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Infectious Polyneuropathies
Varicella-Zoster Virus (chickenpox)
Common viral infection of the peripheral nervous system.
A latent infection persists within neurons in the sensory ganglia of the spinal cord and brain stem, and reactivation leads to a painful, vesicular skin eruption in the distribution of sensory dermatomes (shingles).
Decreased cell-mediated immunity – reactivation of virus.
The virus - transported along the sensory nerves to the skin.
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Acquired metabolic and toxic neuropathies
High prevalence (50-80%) of peripheral neuropathy in individuals with diabetes mellitus
Combination of peripheral and autonomic neuropathy
Pathogenesis
Hyperglycemia causes the nonenzymatic glycation of proteins, lipids, and nucleic acids
advanced glycation end products (AGEs)
interfere with normal protein function
Excess glucose within cells → glucotoxicity
predispose peripheral nerves to injury by reactive oxygen species
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Peripheral Neuropathy in Adult-Onset Diabetes Mellitus
Insulin Resistance and Glucotoxicity
Insulin resistance and glucotoxicity in neurons results in neuronal dysfunction leading to diabetic neuropathy
http://diabeticnewstoday.com/wp/diabetes-awareness/types-of-diabetes/
http://universityhealthnews.com/daily/diabetes/diabetic-neuropathy/
Traumatic Neuropathies
Peripheral nerves are commonly injured during trauma – regeneration occurs, sometimes leads to traumatic neuroma (mass of tangled axonal processes)
Compression neuropathy (entrapment neuropathy)
Peripheral nerves are compressed – symptoms range from numbness, weakness, pain, tingling etc
Carpal tunnel syndrome (compression of the median nerve) – seen in association with pregnancy, edema, hypothyroidism, diabetes mellitus etc.,
Sciatica – compression of sciatic nerve or irritation of the roots of lumbar spinal nerves
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Diseases of Skeletal Muscle
Muscular Dystrophies
Duchenne Muscular Dystrophy
Ion Channel Myopathies
Myopathies Associated with Inborn Errors of Metabolism
Lipid Myopathies
Mitochondrial Myopathies
Inflammatory Myopathies
Toxic Myopathies
Thyrotoxic
Ethanol
Drug-Induced
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Types of Muscle Fibers
Various muscles contract at different speed composed of different types of muscle fibers
Other factors that determine msl fiber type:
Acto-Myosin ATPase Activity
Positively correlated with muscle contraction velocity
Enzymes that are involved in glycolytic or oxidative metabolism
Lactate dehydrogenase
NADH dehydrogenase
Myosin heavy chain isoforms
Type 1, 2A, 2D, 2B etc
Motor neuron → Major determinant of muscle fiber type
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Mnemonic: “one (type 1 fiber) slow (twitch) fat (lipid-rich) red (appearance) ox (oxidative)”
Muscular Dystrophies
Inherited disorders of muscle leading to progressive weakness and muscle wasting.
In advanced cases muscle fibers undergo degeneration and are replaced by fibro fatty tissue and collagen, distinguishing dystrophies from myopathies.
X-linked muscular dystrophy
Duchenne muscular dystrophy (common)
Becker muscular dystrophy
Duchenne muscular dystrophy
Mutations in DMD gene, which encodes dystropin
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Dystrophin (intracellular protein) and the dystrophin-associated protein complex form an interface between the intracellular contractile apparatus and the extracellular connective tissue matrix.
Duchenne muscular dystrophy
Failure to transfer the contraction force from muscle fiber to connective tissue in the absence of dystropin → myocyte degeneration.
Pseudohypertrophy of the muscles of the lower leg - an important clinical finding.
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Varied muscle fiber size, increased endomysial connective tissue, and regenerating fibers (blue hue)
Ion Channel Myopathies (Channelopathies)
Malignant hyperpyrexia (malignant hyperthermia): a rare clinical syndrome characterized by a marked hypermetabolic state triggered by anesthetics
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Ryanodine
Receptor
Pathophysiology:
Mutations in several genes, notably the ryanodine receptor
Upon exposure to anesthetic, the mutant receptor allows uncontrolled efflux of calcium from the sarcoplasm, leading to tetany, increased muscle metabolism, and excessive heat production.
Inflammatory Myopathies
Infectious myositis:
Bacteria, virus, fungi, protozoans etc
Cysticercosis: Taenia solium larvae – cysts in msl
Trypanosomiasis: T. cruzi
Lyme disease – musculoskeletal manifestations
Pyomyositis – HIV infection, diabetes, parasitic infections
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Toxic Myopathies
Thyrotoxic myopathy
Elevated thyroxine levels – hyperthyroidism
Thyroxine – regulates growth and metabolism of many cell types including neuronal and msl cells
Excess thyroxine –
structural changes in motor end plates (MEPs)
↓ acetylcholinesterase leads to ↑ Ach levels causing overstimulation of MEPs → muscle fatigue and weakness
directly ↑ses cAMP in muscle cells leading to ↑ calcium → msl contraction
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Toxic Myopathies
Ethanol Myopathy
Binge drinking of alcohol – rhabdomyolysis, myoglobinuria
Alcohol – impaired IGF-1 signaling
Malnutrition + alcohol consumption – synergistically produce myopathy
Associated with alcoholic neuropathy most of the times
Toxic Myopathies
Drug induced myopathies
Statins
Implicated in reduction of cholesterol
Statin-induced myopathy - an important cause of statin intolerance and the most common cause of statin discontinuation.
Myalgia, myositis, rhabdomyolysis, and asymptomatically increased creatine kinase
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Drug induced myopathies….cont’d
Chloroquine
Used in the treatment of malaria
Chloroquine-induced myopathy
vacuoles in myocytes
most commonly in type 1 fibers
myocyte necrosis
Steroids
Cushing syndrome or therapeutic use of steroids like corticosteroids (cortisone, dexamethasone, prednisone) – steroid myopathy
weakness in the proximal msls of upper and lower limbs
atrophy, fat deposition, necrosis, rhabdomyolysis etc
Diseases of the Neuromuscular Junction
Myasthenia Gravis
Autoimmune disorder of NMJ
Fluctuating fatigue and weakness that improve after a period of rest and after administration of acetylcholinesterase inhibitors
Muscles with small motor units, such as ocular muscles - often affected.
Pathophysiology
Autoantibodies against acetylcholine (ACh) receptors present in the motor end plate
↓ in functional ACh receptors ↓ muscle contraction by limiting depolarization
Closely associated with lesions in thymus (Helper T cells activate B cells to produce autoantibodies)
Myasthenia Gravis…cont’d
A 70–90% decrease in the number of receptors per end plate in affected muscles
Bound antibody evokes immune-mediated destruction of the end plate.
Bound antibody also activates complement-mediated destruction of the postsynaptic region, resulting in simplification of the end plate.
Lambert – Eaton Myasthenic Syndrome
Commonly associated with small-cell lung cancer
Affected individuals develop proximal muscle weakness and autonomic dysfunction
While Ach receptors are targeted by immune system in myasthenia gravis, in LEMS, ACh release from nerve cells is interfered due to a mutation in calcium channel
Calcium entry into nerve cells is required for ACh release
No clinical improvement with anticholinesterase agents
Myostatin Inhibition (FYI)
Inhibiting myostatin and thereby increasing muscle mass – possible application for treating patients with various types of muscular dystrophy ???
Summary
Define a motor unit, describe the general types of peripheral nerve injury and contrast denervation atrophy vs. myopathy.
Describe the characteristics of the two muscle fiber types.
Describe the neuropathies caused by infectious pathogens - Guillain-Barre syndrome and chickenpox.
Describe the metabolic and nutritional neuropathies - diabetes mellitus and thiamine deficiency.
Describe traumatic neuropathies - compression neuropathy.
Describe the pathophysiology of motor neuron disease, spinal muscular atrophy, X-linked muscular dystrophies, dystrophy vs. myopathy
Describe channelopathies and explain how alcohol, statins, steroids and chloroquine can cause myopathy.
Explain the pathophysiology of myasthenia gravis and differentiate it from Lambert-Eaton myasthenic syndrome.
