Gary C. Sieck, Ph.D., studies the neural control of breathing muscles, including the diaphragm and airway smooth muscle, and how these muscles adapt to a variety of conditions.
Dr. Sieck has developed an extensive array of state-of-the-art physiological and biomedical engineering techniques to explore the interaction between motor neurons in the nervous system and the muscle fibers they innervate. These techniques include confocal imaging of motor neurons in the spinal cord; laser-capture microdissection for analysis of mRNA expression in single cells; biomechanical measurements at various levels of muscle performance, including single muscle fiber contractions; determinations of contractile protein expression in muscle fibers; viral-mediated gene transfer in motor neurons and muscle fibers; real-time imaging of mitochondrial dynamics and function; and exploration of cell signaling pathways mediating neuromuscular transmission and excitation-contraction coupling.
Dr. Sieck's research has been continuously funded by multiple grants from the National Institutes of Health for more than 35 years.
- Neural control of the diaphragm muscle. This research focuses on motor units, which comprise 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.
- Diaphragm muscle weakness. Diaphragm muscle weakness is a hallmark of a number of diseases (for example, neurodegenerative diseases, chronic obstructive pulmonary disease), conditions (for example, hypothyroidism, cachexia, sarcopenia) and treatments (for example, mechanical ventilation, corticosteroids, chemotherapy). Such weakness, when it occurs, may severely limit the mechanical performance of the diaphragm and compromise an individual's ability to clear the airways, or under extreme conditions, his or her ability to breathe. Dr. Sieck's research is examining basic mechanisms underlying weakness in different muscle fiber types. In this regard, he is focusing on the cross-bridge, which is the structural interaction between myosin and actin, and the essential units of force generation in muscles. Four different types of myosin heavy chains exist that comprise different muscle fiber types. Dr. Sieck was the first to describe fiber type differences in cross-bridge cycling kinetics and the mechanical and energetic consequence of changes in myosin heavy chain expression and content in diaphragm muscle fibers. The results of his studies clearly indicate fiber type differences in the impact of diseases, conditions and treatments on myosin heavy chain expression and content that affect muscle fiber cross-bridge cycling and result in muscle weakness.
- Respiratory muscle sarcopenia. Dr. Sieck's laboratory is exploring mechanisms underlying sarcopenia (age-related muscle fiber atrophy and weakness) in diaphragm muscle fibers, and how this impacts respiratory neuromotor control. This research focuses on changes at the level of phrenic motor neurons (for example, motor neuron autophagy) as well as at type-identified diaphragm muscle fibers (control of net protein balance). This research also builds on the basic information gained from his studies on diaphragm neuromotor control. For example, Dr. Sieck has provided evidence that there is a loss of phrenic motor neurons in old age, resulting in denervation of type IIx/IIb fibers comprising more fatigable fast-twitch motor units that are required for high force, nonventilatory motor behaviors of the diaphragm (for example, coughing and sneezing). He hypothesizes that brain-derived neurotrophic factor (BDNF) and its high-affinity receptor (TrkB) signaling is involved in motor neuron survival and that disruptions in this signaling pathway may underlie age-related death of the specific motor neurons that comprise more fatigable fast-twitch motor units. At the same time, continued BDNF/TrkB signaling in phrenic motor neurons innervating type I and IIa muscle fibers, comprising fatigue resistant slow- and fast-twitch motor units, ensures their integrity in accomplishing essential ventilatory behaviors of the diaphragm. At the level of muscle fibers, Dr. Sieck hypothesizes that sarcopenia and phrenic motor neuron death results in the removal of the nerve-derived release of neuregulin (NRG), a trophic factor that signals via the ErbB family of tyrosine kinase receptors. Removal of NRG/ErbB signaling results in atrophy of type IIx/IIb fibers. These studies will provide potential therapeutic targets to ameliorate sarcopenia and improved the quality of life in old age.
- Functional recovery after cervical spinal cord injury. Upper cervical spinal cord injury often results in complete or partial diaphragm muscle paralysis that may require ventilatory support for patients and is associated with higher morbidity and mortality rates. Clearly, it is important to understand how rhythmic diaphragm muscle activity can be restored in these patients with spinal cord injury. Dr. Sieck's research has shown that at the level of phrenic motor neurons, functional recovery of diaphragm muscle activity is enhanced by promoting the effect of BDNF acting through TrkB. For example, intrathecal BDNF treatment enhances functional recovery of rhythmic diaphragm muscle activity after spinal cord injury. Unfortunately, intrathecal BDNF treatment is associated with significant negative adverse effects that preclude its therapeutic use. As an alternative, Dr. Sieck is exploring the use of locally implanted mesenchymal stem cells that are genetically engineered to produce BDNF. Dr. Sieck has also developed a novel targeted approach to increase TrkB expression in phrenic motoneurons using an adeno-associated virus and thereby promoting functional recovery after spinal cord injury.
- Interaction between mitochondria and sarcoplasmic reticulum in airway smooth muscle. Dr. Sieck's lab is also exploring the neural control of airway smooth muscle, specifically the pathophysiology of airway hyperreactivity (increased force response) and remodeling (increased cell proliferation) characteristic of asthma. This research focuses on control of cytoplasmic calcium and its coupling to mechanical responses (that is, excitation-contraction coupling). Dr. Sieck's lab characterized the basic mechanisms underlying the acetylcholine (ACh)-induced elevation of cytoplasmic calcium, and how these mechanisms are affected by exposure to pro-inflammatory cytokines, as occurs in asthma. He also systematically examined the signaling cascade involved in coupling the transient elevations of cytoplasmic calcium to contractile responses in airway smooth muscle. As in all muscles, increased airway smooth muscle contraction (hyperreactivity) imposes increased energetic demands (ATP hydrolysis) and mitochondrial stress. Dr. Sieck is examining the role of mitochondrial signaling in relation to airway smooth muscle exposure to pro-inflammatory cytokines, reactive oxidants and endoplasmic reticulum stress. Dr. Sieck hypothesizes that this represents a complex physiological signaling cascade that underlies asthma triggering both airway hyperreactivity and remodeling (airway smooth muscle cell proliferation).
Significance to patient care
The long-term goal of Dr. Sieck and his research team is to develop novel therapeutic approaches to counter the effects of neuromuscular disease, critical illness, aging or spinal cord injury on the neural control of the diaphragm muscle, and hyperreactivity of airway smooth muscles in asthma and chronic obstructive pulmonary disease.
- Inaugural fellow, American Physiological Society (FAPS), 2014-present
- Distinguished Alumnus, University of Nebraska Medical Center, 2014
- Editor-in-chief, Physiology, 2012-present
- Vernon F. and Earline D. Dale Professor, Mayo Clinic College of Medicine, 2011-present
- Elected fellow, College of Fellows, American Institute for Medical and Biological Engineering (AIMBE), 2008-present
- Chair, Department of Physiology and Biomedical Engineering, Mayo Clinic, 2001-2013
- President, Association of Chairs of Departments of Physiology, 2010-2011
- Dean, Research Academic Affairs, Mayo Clinic College of Medicine, 2006-2011
- President, American Physiological Society, 2009-2010
- Mayo Distinguished Investigator, Mayo Clinic, 2007