Monthly Archives: April 2019

Supporting breathing in muscular dystrophy

By David P Burns and Ken D O’Halloran, Department of Physiology, University College Cork, Ireland

The respiratory system plays a very important role in maintaining oxygen levels within our blood. The supply of oxygen to our body is necessary to allow the cells in our body to make and use energy (a process called metabolism).

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Respiratory muscle from mdx mice displays signs of muscle damage. When dystrophin is absent from muscle, muscle fibres become damaged during normal cycles of muscle contraction and relaxation. Over time, damaged muscle becomes replaced by fat cells and there is an accumulation of connective tissue resulting in further muscle weakness and hardening of the tissue.

The respiratory system is an integrated organ system that relies on input from our central nervous system (brain and spinal cord). Motor nerves project from our central nervous system and send electrical signals, called action potentials, to our respiratory muscles. These signals activate our respiratory muscles, including the diaphragm (the main pump muscle of breathing) and intercostal muscles, resulting in contraction of these important muscles. The diaphragm and external intercostal muscles contract during inspiration, allowing a negative pressure to be generated within the respiratory system. This negative inspiratory pressure draws air from the atmosphere into our lungs. In our lungs, oxygen that has entered from the atmosphere enters our blood and is transported around our body to our cells. The same system is crucial for the excretion of carbon dioxide, a by-product of cellular metabolism, during expiration.

Poor performance or weakness of our respiratory muscles can result in impaired respiratory function, limiting how much air enters and leaves our lungs. Respiratory muscle weakness can occur due to a loss of muscle mass, such as in cancer cachexia and age-related sarcopenia.

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Recording of the electrical activity of diaphragm muscle (electromyogram) in an anaesthetised mouse.

Breathing with neuromuscular disease

Researchers at University College Cork in Ireland are focusing on respiratory muscles and how they are controlled by the central nervous system in neuromuscular diseases such as muscular dystrophy. Duchenne muscular dystrophy (DMD) is a genetic disease that causes severe muscle weakness in boys. The diaphragm has reduced strength in DMD due to the absence of an important structural protein found in muscle, called dystrophin. As boys with DMD grow older they have difficulty with their breathing. Initially, this occurs during sleep with the development of sleep-disordered breathing and later problems also present during wakefulness.

Studies led by researchers David Burns and Ken O’Halloran aim to understand the effects of a weakened diaphragm (due to a lack of dystrophin) on respiratory system performance in animal models of muscular dystrophy. Currently, the group is trying to understand ways in which the body can compensate for a mechanically weakened diaphragm muscle, with the aim of enhancing or at least protecting these compensatory mechanisms that support normal breathing.

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Healthy diaphragm muscle is composed of a blend of different types of muscle fibres (shown above as blue, red, black and green muscle fibres). Each muscle fibre type has its own unique characteristics. The blue muscle fibres (Type I) can generate small amounts of force when they contract and are resistant to fatigue. The green fibres (Type IIB) can generate large forces such as those required during coughing or clearing of our airways. Type IIB are not resistant to fatigue. Top left traces show diaphragm electromyogram activity. Bottom right shows diaphragm muscle contractions in response to increasing stimulation frequency.

New research published by the group in The Journal of Physiology (1) has revealed that the capacity of the respiratory system to increase breathing when challenged is preserved in an animal model of muscular dystrophy, the mdx mouse. This is an interesting finding given the diaphragm muscle of mdx mice can generate only half the force of a non-diseased diaphragm.

Compensation to support breathing

To understand how mdx mice can breathe at levels similar to the control group of mice, the group measured the inspiratory pressure generated by the system during normal and near maximal breathing. In order to examine how the central nervous system controls weakened respiratory muscles, the group measured the electrical signals in the diaphragm and intercostal muscles (which were sent along motor nerves from the central nervous system). These unique studies have revealed that although the diaphragm muscle of mdx mice is weakened and displays less electrical activity than the control group of mice, the mdx mice can generate inspiratory pressures similar to control mice. These novel findings reveal a form of compensation that supports breathing in young mdx mice.

Retaining the capacity to generate peak inspiratory pressure during the course of aging and in disease states such as DMD is essential during periods of increased demand on our respiratory systems. Current studies by Burns and O’Halloran aim to understand the specific mechanisms responsible for this compensatory support in young mdx mice and to determine if this compensation is preserved or lost over the course of this progressive disease. Therapeutic and rehabilitative strategies that promote compensatory support of breathing in muscular dystrophy may provide support for maintaining respiratory function in patients as the disease progresses.

References:

  1. Burns DP, Murphy KH, Lucking EF, O’Halloran KD (2019) Inspiratory pressure-generating capacity is preserved during ventilator and non-ventilatory behaviours in young dystrophic mdx mice despite profound diaphragm muscle weakness. The Journal of Physiology 597(3):831-848.