Muscle Disease

                        Muscle Disease.

                     PKGhatak, MD

The human body has three types of muscles.

1.The Striated skeletal muscle.

2. Cardiac muscle is also striated but it works involuntarily. Cardiac muscle fibers are joined together without partitions and contract in unison. It is known as the syncytial muscle.

3. Smooth muscle has no striation and is a non-voluntary muscle. It is present in the wall of arteries, Gastrointestinal and genitourinary tracts and sphincters,

When a muscle is mentioned without any qualification it is the skeletal muscle. Skeletal muscle disease is easier to understand if the basic structure and function of muscle are understood.

Basic muscle structure.

Muscles are a collection of muscle cells, usually referred to as muscle fibers. Muscle fibers are long and cylindrical and arranged in bundles and the end of fibers are attached to bones or joint capsules. Muscles are very vascular and are equipped with abundant mitochondria and multiple nuclei. The motor nerve fibers to muscles originate at the anterior horn cells of the spinal cord. Skeletal muscles contract under voluntary control and in abnormal conditions they can also contact their own but such contractions result in shivering or muscle twitching. Respiratory muscles work incessantly without conscious effects and also on demand. The detailed arrangement of the muscle bundle is shown above diagram.

Function of muscle.

Muscles shorten by contraction and result in ambulation or joint movements and the heat generated by muscle action increases body temperature.

How muscle contacts.

The motor nerve transmits nerve impulses at the neuromuscular junction. The impulse propagated along the sarcolemma to the entire length of the muscle. As a result, calcium ions from the sarcoplasmic reticulum are released and the released calcium iron enters into the muscle cells. This generates an action potential. Calcium ion binds with a protein called Troponin which pulls Myosin molecules towards Actin molecules. Actin and myosin molecules slide against each other causing shortening of muscle fibers. This action requires energy and is supplied by ATP. At the end of muscle contraction, the process is reversed and muscle fibers return to the relaxed state.

Diseases of the skeletal muscle.

From the above paragraph, it is clear that muscle disease may arise from the muscle fiber itself and is called Primary Muscle disease. Some other diseases may damage muscle fibers or their functions and these are Secondary muscle diseases.

Primary Muscle Disease.

Primary muscle diseases are 1. Hereditary Mitochondrial muscle diseases and 2. Congenital Myopathies.

 1. Hereditary Mitochondria muscle diseases.

Inherited defective genes that encode energy producing enzymes when passed to a child the disease manifests at birth or later in life. The muscles are weak and disease is initially detected in eye muscles and then progresses through the entire body.

A. Leigh syndrome. The cytochrome enzyme system is defective in Leigh syndrome and eye muscle weakness develops in infancy. Weakness of the whole body soon follows. Associated heart abnormalities and low position of ears and high forehead is a distinct facial features. The child hardly can reach 5 yrs. of age.

B. Keans-Sayer Syndrome. The mutated gene encodes Oxidative phosphorylation. A child may normally develop to early teens then develops drooping eyelids, and soon one or both sided intermittent weaknesses develop. Other features are ataxia, deafness, heart rhythm disturbances and hormone deficiencies.

C. Melas syndrome. The defect is in the NADPH enzyme system. Muscle weakness begins at about age 40 yrs. Seizures, mental changes, migraine, lactic acidosis and strokes develop.

 2. Myopathy.

The main symptom is muscle weakness, other less common symptoms are muscle cramps, stiffness and walking difficulties.

1. Inherited Muscular Dystrophy.

The general term for this entity is Muscular Dystrophy. Progressive muscle weakness is due to muscle degeneration. In the early stage of the disease, regeneration of muscle is seen but later lost. Various from of disabilities develop and death is generally from respiratory failure.  Muscular dystrophies have several clinical types based on the onset and progression of the disease and the genetic defects.

Clinical Types.

      Duchenne Muscular Dystrophy

     . Becker Muscular Dystrophy. ...

• Congenital Muscular Dystrophy. ...

• Myotonic Muscular Dystrophy. ...

• Limb-Girdle Muscular Dystrophy. ...

• Facioscapulohumeral Muscular Dystrophy. ...

• Emery–Dreifuss Muscular Dystrophy. ...

• Distal Muscular Dystrophy.

Duchenne Muscular dystrophy is more familiar to people of the US due to Jerry Lewis MDA Labor Day Telethon. The inheritance is sex link X chromosome in recessive mode, only male child is affected by this genetic disorder. 1 in 3 - 5 thousand male children is affected. In recent years a new class of drug has been approved for the treatment of Duchenne dystrophy. The Antisense Oligonucleotides drug acts as a bridge over the missing exons (functioning genes) like a Band-Aid that produces the protein needed for the repair of muscles. The latest approved drug is a small-molecule Sunitinib.

Secondary Muscle disease:

1. Acquired Muscular Dystrophy.

Many diseases can damage and destroy skeletal muscle. Diseases or agents producing myopathy can be broadly grouped as Endocrine and Metabolic, Drug induced, Inflammatory, Prolonged illness, Neurological, Collagen vascular, Autoimmune and Unknown causes.

One common feature of this group of myopathies is the rapid onset. Inflammatory myopathy requires muscle biopsy to identify a specific entity. Autoimmune and other systemic diseases are identified from clinical and laboratory tests.

2. Dermatomyositis and Polymyositis are often secondary to a malignant process or a viral induced autoimmune disease. The skin rashes of Dermatomyositis appear around the eyes and over the knuckles and elbows and are reddish in color. The visible capillaries over the rough fingernail folds are an important diagnostic clue. In Polymyositis large groups of muscle are affected and weakness of shoulder and pelvis girdles is an important feature.

3. Inclusion body myopathies (IBM) are a common muscle disease of elderly people. Progressive weakness of fingers, wrists, muscles on the anterior aspect of the thigh and legs develop over time and atrophy of muscles follows. Antibodies to Cytosolic 5- nucleotidase-1A, when present indicates an autoimmune component. Congo-red stained rimmed vacuoles and areas of muscle necrosis surrounded by the inflammatory cell are seen in muscle biopsy. Treatment is unsatisfactory.

4. Collagen vascular disease myopathy is also common. Muscle weakness and atrophy in muscles of the face neck and neck in Scleroderma is a distinct feature. Systemic lupus and Rheumatoid arthritis and mixed connective tissue diseases also have muscle weakness and different degrees of muscle atrophy.

 5. Neurological and Neuromuscular disease.

Cerebrovascular accident, otherwise known as stroke, is a good example of how muscle undergoes wasting, stiffness, hyperreflexia and loss of function. These symptoms are due to the loss of inhibitory influence of upper motor neurons (UMN) on lower motor neurons (LMN). Prolonged disuse leads to muscle atrophy and contracture.

Spinal cord injury.

In spinal cord lesions, none of the muscle abnormalities above the site of spinal cord injury show any weakness. At the site of injury, it produces complete loss of muscle function and loss of resting tone of muscles. Below the site of injury, muscles show features of Upper Motor Neuron lesion as described under UMN lesion.

Peripheral nerve

Peripheral nerve lesion produces complete loss of muscle function innervated by that nerve.

Other systemic diseases.

Multiple sclerosis. Parkinson's disease. Meningitis and encephalitis and degenerative neuronal diseases produce muscle loss of function depending on the site of the lesion in the brain, spinal cord, or peripheral nerves.

Amyotrophic Lateral Sclerosis (ALS)

ALS is better known in the USA as Lou Gehrig's disease. It is a motor neuron disease involving both upper and lower motor neurons. ALS usually develops in the past middle life and 5 to 10 % of ALS cases are inherited as an autosomal recessive disease. The initial symptom is muscle twitching at rest which can be demonstrated by gently tapping muscles. Weakness of muscle develops gradually and affects all skeletal muscles of the body. The death is from respiratory failure.

Multifocal motor neuron disease may resemble ALS but it is limited to one side of the body and muscles of the fingers and hands are more affected and with treatment, the condition improves. 

6. Endocrine and Metabolic diseases.

Hyperthyroidism produces muscle wasting and weakness of pelvic and shoulder girdle muscles. Hypothyroidism produces weakness of the shoulder and gluteal muscles due to decreased metabolic rate and energy supply to muscles is limited.

Familial periodic paralysis.

Familial periodic paralysis is due to the mutation of genes that regulate sodium and calcium channels of the neurons. This is an intermittent paralytic disease. Muscles are hypotonus, weak and fail to contract during an attack but function normally in between times.

Hypokalemic periodic paralysis is due to the fall of serum Potassium. The symptom usually develops in adolescence precipitated by a rich carbohydrate meal or strenuous exercise. An attack may last hours to days. Generalized weakness develops later in life.

 In contrast, high serum Potassium periodic paralysis starts in early childhood and attacks are more frequent but last a shorter period.

Glycogen storage disease type VII 

This inherited glycogen storage disease produces muscle weakness due to failure of glycogen utilization in the muscles.

7. Neuromuscular junction.

Myasthenia gravis is an autoimmune disease triggered probably by a viral infection. Antibodies bind with the neurotransmitter Acetylcholine and acetylcholine level falls. Depolarization of the muscle is prevented because of a lack of acetylcholine. During rest, some Acetylcholine is generated and the function returns. But on repeated muscle use paralysis develops again. The drooping of eyelids and ophthalmoplegia are initial symptoms. Paralysis of other muscles, notably to head and neck muscles develops slowly. Speech, drinking, and eating becomes problematic and respiratory muscle paralysis follows. Early diagnosis and prompt immunosuppressive therapy can arrest the disease and improve the functional status of muscles.

Eaton -Lambert disease

Eaton Lambert disease is another example of neurotransmitter disease. Reduced acetylcholine release from the presynaptic nerve terminals due to antibodies to voltage-gated calcium channels produces muscle paralysis. Patients with Small Cell Carcinoma of the lung exhibit this paralysis frequently, other lung carcinoma rarely causes this disease. In contrast to Myasthenia, Eaton-Lamber disease affects the muscles of the legs initially. Head neck muscle may be involved later but much less severely, respiratory muscles are spared. Leg muscle function improves with repeated muscle movements.

Guillain-Barre syndrome.

It is due to antibodies damaging the myelin sheath and axon of nerve fibers. Leg and arm muscles are primarily affected. Because peripheral nerves are mixed nerves, numbness and tingling also develop.

8. Drugs causing muscle paralysis.

 Action on the respiratory center of the brain.

Opioids, Fentanyl and other semisynthetic opioid derivatives have taken so many lives in recent years. The depressive effects of these compounds make the respiratory center insensitive to rising CO2, falling blood pH and hypoxia. In the end the respiratory muscles stop functioning causing death.

9. Therapeutic muscle paralysis.

 It is extremely unpleasant and stressful for a conscious patient to be intubated and mechanically ventilated. Patients fight for air and try to breathe faster than in the ventilator settings. Muscle-paralytic agent Succinylcholine is used to eliminate the patient's effort and completely take over the ventilation by mechanical means. Succinylcholine causes depolarization of the motor- endplate; and because the drug is not immediately broken down by the enzyme cholinesterase, the depolarization persists and muscles are kept in a paralyzed state as long as needed. Eventually, Pseudocholinesterase, another enzyme, breaks down succinylcholine but at a slower rate.

Many derivatives of Tubocurarine combine with receptors of acetylcholine at the motor endplate and produce partial skeletal muscle paralysis and are used as a remedy for muscle stiffness in Upper neuron paralysis. Antibiotics Neomycin, Streptomycin and Polymyxin can potentiate neuromuscular blocking agents by competitive synergistic effect. Centrally active muscle relaxants Mephenesin, Meprobamate, Benzodiazepines and other CNS depressive drugs can decrease intraneuronal activities and block parasympathetic neurotransmission.

 Statins:

Statin is a widely used medicine as a treatment for lipid abnormalities. Many patients complained of nocturnal leg cramps, leg pain and proximal muscle weakness and getting in and out of an automobile becomes hazardous. Researchers discovered that muscle weakness and related side effects of statin are likely due to its effect on the energy production centers, or mitochondria of muscle cells. The intermediate metabolite Lactone interferes with mitochondrial function. Switching to a water soluble statin or reducing the dose of statin may control symptoms, otherwise, discontinuation of statin is required. Statin also produces narcotizing autoimmune myopathy due to antibodies produced against enzyme HMG coenzyme A. This is less common but stopping statin does not stop muscle necrosis.

10. Myositis. 

Many viruses can infect muscles producing muscle pain. Dengue fever causes worse types of backache.

 Myositis Ossificans is a less common disease.

A damaged muscle heals by having connective tissue from adjacent structures infiltrate the muscle. Occasionally bone generating stem cells enter muscles and produce lumps and these lumps are painful and interfere with muscle function.

 11. Rhabdomyolysis.

Crush injury of muscle and compression injury in Compartment syndrome can produce muscle necrosis.  Released Myoglobin from the damaged muscles by blocking glomeruli capillaries and renal failure.

12. Tumors of the skeletal muscle.

Fortunately, tumors of muscle are rare. Rhabdomyosarcoma is one malignancy, seen in all ages and carries a bad prognosis. 

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