Gary C. Sieck, Ph.D., studies the cell signaling mechanisms that underlie muscle performance. In particular, he focuses on regenerative processes that can be enhanced to mitigate a variety of acute and chronic disease conditions. Dr. Sieck has developed an extensive array of state-of-the-art physiological, molecular and biomedical engineering techniques to explore cell signaling pathways. These techniques include:
- Real-time confocal imaging
- Laser-capture microdissection and multiplex in situ hybridization for analysis of mRNA expression in single cells
- Biomechanical measurements at various levels of muscle performance including single muscle fiber contractions
- Cell signaling pathways mediating neuromuscular transmission and excitation-contraction coupling
- Real-time imaging of mitochondrial dynamics and function
- Determinations of contractile protein expression in muscle fibers
- Viral-mediated gene transfer in motor neurons and muscle fibers
- Engineered mesenchymal stem cell delivery of trophic factors
Dr. Sieck's research has been continuously funded by multiple grants from the National Institutes of Health for more than 38 years.
Motor neurons and neuromuscular control. Research in Dr. Sieck's Cell and Regenerative Physiology Laboratory focuses on motor neurons and neuromotor control of muscle contraction. Specifically, the lab explores the structure and function of diaphragm muscle motor units that comprise phrenic motor neurons located in the cervical spinal cord and the group of muscle fibers they innervate. Motor units are 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 diaphragm motor units 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 and mitochondrial volume densities 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, expulsive motor behaviors of the diaphragm.
Dr. Sieck's lab is also exploring structural and functional changes in phrenic motor neurons associated with embryonic and early postnatal development as well as with old age. For example, in old age there is a loss of larger phrenic motor neurons that results in a loss of more-fatigable fast twitch motor units that are required for high-force, expulsive motor behaviors of the diaphragm such as coughing and sneezing. Dr. Sieck's team is exploring whether the age-related loss of phrenic motor neurons is due to altered mitochondrial function or changes in motor neuron autophagy and mitophagy. 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 comprise more-fatigable fast twitch diaphragm motor units. Dr. Sieck has also shown that the BDNF-TrkB signaling pathway is involved promoting neuroplasticity in synaptic input to phrenic motor neurons and recovery of function after spinal cord injury. Upper cervical spinal cord injury often results in complete or partial diaphragm muscle paralysis that may require ventilatory support and is associated with higher morbidity and mortality rates. It is important to understand how rhythmic diaphragm muscle activity can be restored in patients 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 as well as 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.
- Muscle weakness. Dr. Sieck examines basic mechanisms underlying muscle fiber atrophy and weakness under a variety of conditions and diseases. Muscle weakness is a hallmark of a number of diseases, such as neurodegenerative diseases and chronic obstructive pulmonary disease; conditions, such as aging, hypothyroidism, cachexia and sarcopenia; and treatments, such as corticosteroids and chemotherapy. Such weakness, when it occurs in the diaphragm muscle, may severely limit the muscle's mechanical performance and compromise patients' ability to clear their airways, or under extreme conditions, their ability to breathe. Dr. Sieck's research team focuses on the basic unit of mechanical force in muscle fibers — the cross-bridge. At the molecular level, Dr. Sieck explores the activation of muscle contraction via elevation of cytosolic calcium (excitation and contraction coupling), the generation of mechanical force and the energetics of four different types of myosin heavy chains that comprise different muscle fiber types. Dr. Sieck's laboratory 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 from Dr. Sieck's research clearly indicate fiber type differences in the impact of diseases, conditions and treatments on myosin heavy chain expression that affect muscle fiber cross-bridge cycling and result in muscle weakness. One example of muscle weakness that Dr. Sieck's lab is exploring is sarcopenia, the age-related atrophy and weakening of muscle fibers. In the diaphragm muscle, sarcopenia impacts the ability of older individuals to clear their airways, increasing their risk for airway infections. The results of Dr. Sieck's studies will provide potential therapeutic targets to mitigate the functional impact of sarcopenia and improve quality of life in old age.
Interaction between mitochondria and endoplasmic reticulum. Dr. Sieck is also exploring the pathophysiological response to inflammation. In airway smooth muscle, exposure to pro-inflammatory cytokines triggers airway hyperreactivity (increased force response) and remodeling (increased cell proliferation) characteristic of asthma. Dr. Sieck's research in this area focuses on the control of cytoplasmic calcium release from the endoplasmic reticulum and its coupling to both mechanical responses (that is, excitation-contraction coupling) and mitochondrial O2 consumption (excitation-energy coupling). Dr. Sieck's lab characterized the basic mechanisms underlying the acetylcholine-induced elevation of cytoplasmic calcium, and how these mechanisms are affected by exposure to pro-inflammatory cytokines, as occurs in asthma.
Dr. Sieck's lab is also systematically examining the signaling cascade that couples 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's research has shown that exposure to pro-inflammatory cytokines induces production of reactive oxidant species (ROS) that results in protein unfolding and endoplasmic reticulum (ER) stress. Activation of this ER stress pathway results in a reduction in the expression of the mitochondrial fusion protein mitofusin (Mfn-2) that is important for tethering mitochondria to the ER and promoting mitochondrial calcium influx. The disruption of the interactions between mitochondria and the ER reduces mitochondrial O2 consumption and ATP production but further increases ROS formation leading to a vicious cycle of ROS production and cellular injury. Dr. Sieck hypothesizes that this ER stress pathway and the vicious cycle it triggers can be mitigated by targeted production of ROS scavengers, chemical chaperones or Mfn-2 expression to facilitate mitochondrial-ER tethering. Dr. Sieck's team is also investigating the involvement of this signaling pathway in other inflammatory diseases including neurodegenerative diseases, ischemia and reperfusion injury in the heart, and diabetes-induced myopathy.
Significance to patient care
The long-term goal of Dr. Sieck's lab is to develop novel therapeutic approaches to counter the effects of acute and chronic diseases including asthma, chronic obstructive pulmonary disease, neuromuscular disease, aging, heart failure and spinal cord injury.
- Inaugural fellow, American Physiological Society, 2014-present
- Member, Council of Faculty and Academic Societies, American Association of Medical Colleges, 2013-present
- Editor-in-chief, Physiology, 2012-present
- Vernon F. and Earline D. Dale Professor, Mayo Clinic College of Medicine and Science, 2011-present
- Chair, Healthcare Systems Engineering Industry Advisory Council, Lehigh University, 2010-present
- Chair, Advisory Council, Center for Arctic Physiology & Medicine, University of Tromso (Arctic University of Norway), 2008-present
- Elected fellow, College of Fellows, American Institute for Medical and Biological Engineering, 2008-present
- Recipient, Distinguished Service Award, Association of Chairs of Departments of Physiology, 2019
- Distinguished alumnus, University of Nebraska Medical Center, 2014, 2019
- Lecturer, Joy Goodwin Distinguished Lecture, Auburn University, 2018
- Lecturer, Julius H. Comroe, Jr., Distinguished Lecture, American Physiological Society, 2016
- Chair, Department of Physiology and Biomedical Engineering, Mayo Clinic, 2001-2013
- William E. Schiesser Distinguished Lecture, Department of Chemical and Biomolecular Engineering, Lehigh University, 2010
- President, American Physiological Society, 2009-2010
- President, Association of Chairs of Departments of Physiology, 2010-2011
- Dean, Research Academic Affairs, Mayo Clinic College of Medicine, 2006-2011
- Consultant, Department of Physiology & Biomedical Engineering
- Consultant, Department of Anesthesiology and Perioperative Medicine
- Consultant, Department of Physical Medicine & Rehabilitation
- Professor of Anesthesiology
- Professor of Physiology
- Fellow - NIH Postdoctoral Fellow (Neurophysiology) School of Medicine, University of California, Los Angeles
- PhD - Physiology and Biophysics University of Nebraska Medical Center, University of Nebraska, Omaha
- BS - Zoology University of Nebraska, Lincoln