Neural Control of the Diaphragm Muscle

The Cell and Regenerative Physiology Laboratory's research on neural control of the diaphragm muscle focuses on motor units. These units include a phrenic motor neuron located in the cervical spinal cord and the group of diaphragm muscle fibers it innervates as the essential elements of neural control. Thus, as a phrenic motor neuron is activated by synaptic input, diaphragm muscle fibers within the motor unit are excited and contract as a unit.

The mechanical and energetic properties of the diaphragm motor unit vary considerably, and different motor unit types are recruited to accomplish a wide range of motor behaviors. Differences in mechanical and fatigue properties of diaphragm motor units are the result of expression of different contractile proteins in corresponding muscle fiber types.

Dr. Sieck's laboratory was the first to characterize the contractile and fatigue properties of different diaphragm motor unit types and to show how these motor units are recruited to accomplish different ventilatory and higher force, nonventilatory motor behaviors of the diaphragm.

In addition to studying diaphragm muscle fibers, Dr. Sieck's research team focuses on the structure and function of phrenic motor neurons. Changes at the phrenic motor neuron level can substantially impact neuromuscular control. For example, in old age there is a loss of larger phrenic motor neurons that results in denervation of type IIx and IIb fibers. These fibers compose the more fatigable fast twitch motor units required for high-force, expulsive motor behaviors of the diaphragm such as coughing and sneezing. Dr. Sieck's research team is determining whether phrenic motor neuron loss is due to altered mitochondrial function or changes in motor neuron autophagy, mitophagy or both.

Dr. Sieck hypothesizes that brain-derived neurotrophic factor (BDNF) signaling through the high-affinity TrkB receptor is involved in motor neuron survival and that disruptions in this important signaling pathway underlie age-related death of larger phrenic motor neurons that compose more-fatigable fast twitch diaphragm motor units.

Dr. Sieck has also shown that the BDNF/TrkB signaling pathway is involved in promoting neuroplasticity in synaptic input to phrenic motor neurons and recovery of function after spinal cord injury. Complete or partial diaphragm muscle paralysis that may require ventilatory support occurs in people with upper cervical spinal cord injuries and is associated with higher morbidity and mortality rates.

The Cell and Regenerative Physiology Lab is focused on understanding how rhythmic diaphragm muscle activity can be restored in people with spinal cord injury. Dr. Sieck's research team has shown that at the level of phrenic motor neurons, functional recovery is enhanced by intrathecal BDNF treatment and the use of locally implanted mesenchymal stem cells that are genetically engineered to produce BDNF. Dr. Sieck's team has also developed a novel targeted gene therapy approach to increase TrkB expression in phrenic motor neurons using an adeno-associated virus.