The overall goal in our lab is to identify the etiologies of muscle fatigue and the physiological processes that limit human performance in health, aging, and disease. Research in our lab is particularly novel because we adopt an integrative and translational approach employing multiple techniques to study fatigue and the limits of human performance in the whole limb down to the cellular and molecular levels. We also investigate the adaptive response to exercise training with the goal of developing targeted interventions to improve muscle power output, muscle size (hypertrophy), and fatigability in both healthy and clinical populations.
Our research philosophy is to conduct hypothesis-driven studies where the experimental approach is driven by the research question rather than the comfort and expertise with a particular technique. As a result, several state-of-the-art techniques are available to members in our lab, including: 1) skeletal muscle bioenergetics assessment in vivo (31P-MRS) and in vitro (epifluorescence microscopy), 2) human muscle biopsy procedure, 3) isolation and assessment of muscle fibers and arterioles from biopsies, 4) protein isoform identification (SDS-PAGE, western blot, immunohistochemistry), 5) in vivo assessment of contractile properties, voluntary activation, and corticospinal excitability (TMS, E-stim, surface EMG), and 6) muscle tissue oxygenation (NIRS) and blood flow (Doppler ultrasonography).
Whole Muscle Mechanics
Skeletal muscle produces movement by converting chemical energy into mechanical energy through the hydrolysis of ATP. The total energetic demand of this process is the sum of the ATP hydrolyzed for ion transport to maintain cell excitability (Na+/K+ ATPase), calcium handling in the sarcoplasmic reticulum (SR-Ca2+ ATPase), and the chemo-mechanical transduction of the myosin–actin interaction (myofibrillar ATPase). Consequently any alteration to the mechanics of the contraction, such as force, velocity, power, contractile frequency, or duty cycle, will inevitability change 1) the energetic demand on the muscle and 2) the rate at which fatigue develops (Sundberg & Fitts, 2019). Our lab uses both custom engineered (Sundberg and Bundle, 2015; Sundberg et al. 2019) and off-the-shelf ergometers/dynamometers (Sundberg et al. 2017; Sundberg et al. 2018) for accurate assessment of whole muscle mechanics. The video is an example of a custom ergometer fabricated by Dr. Sundberg as part of his master's thesis work in Dr. Matt Bundle's Biomechanics lab.
Single Fiber Contractile Mechanics
All observations made at the whole muscle level in vivo are influenced by factors that may be originating anywhere along the motor pathway. Our lab uses the chemically-skinned fiber preparation, in which the cell membrane of biopsied muscle fibers is permeabilized, to allow precise control over the intracellular milieu surrounding the contractile proteins. This preparation has the advantage of being able to investigate how individual molecules such as fatigue-inducing metabolites (Sundberg et al. 2018) or calcium (Teigen et al. 2020) alter contractile function. In our lab, the single fiber preparation is used to study shortening velocity, force, power, and the low- to high-force transition of the cross-bridge cycle in fibers isolated from both healthy and clinical populations. The figure is data showing that the peak power of fast MHC II muscle fibers are 2-fold greater in fibers from young (23 yrs) compared with old men (82 yrs), which can be explained entirely by the age differences in fiber size. It also shows that a fatigue-mimicking condition (pH 6.2 + 30 mM Pi) causes marked decrements in power, but that the relative reduction did not differ with age indicating that the age-related increase in fatigability is not due to an increased sensitivity of the cross-bridge to these metabolites (Sundberg et al. 2018).
Whole Muscle Bioenergetics - 31P-MRS
Skeletal muscle, unlike any other tissue in the body, has the profound ability to increase its energetic demand over 100-fold from rest to maximal activation. Because intracellular [ATP] in quiescent muscle is low (~5-6 mmol/kg wet weight or ~8.2 mM), this large energetic demand would deplete ATP in <2 seconds and cause the contractile proteins to enter a state of rigor. Clearly, this never happens in vivo, and rather, the body is able to maintain intracellular [ATP] relatively stable via the synchronized activation of the creatine kinase and adenylate kinase reactions, glycolysis and oxidative phosphorylation. A fundamental consequence of relying on anaerobic metabolism for ATP resynthesis, however, is that the muscle fatigues rapidly (Sundberg and Bundle, 2015; Sundberg et al. 2017). Our lab measures intramuscular bioenergetics and the accumulation of fatigue-inducing intracellular metabolites (hydrogen, inorganic phosphate, diprotonated phosphate) during high-intensity exercise via phosporus nuclear magnetic resonance spectroscopy (31P-MRS). The figure is data showing the close association between power loss during a 4-minute dynamic fatiguing knee extension exercise and the accumulation of hydrogen (pH), inorganic phosphate, and diprotonated phosphate (Sundberg et al. 2019).