Browsing by Author "Spangenburg, Espen E."

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    Effects of fasting on isolated murine skeletal muscle contractile function during acute hypoxia
    (Public Library of Science, 2020-04-23) Schmidt, Cameron A.; Goldberg, Emma J.; Green, Tom D.; Karneka, Reema R.; Brault, Jeffrey J.; Miller, Spencer G.; Amorese, Adam J.; Yamaguchi, Dean J.; Spangenburg, Espen E.; McClung, Joseph M.; Anatomy and Cell Biology, School of Medicine
    Stored muscle carbohydrate supply and energetic efficiency constrain muscle functional capacity during exercise and are influenced by common physiological variables (e.g. age, diet, and physical activity level). Whether these constraints affect overall functional capacity or the timing of muscle energetic failure during acute hypoxia is not known. We interrogated skeletal muscle contractile properties in two anatomically distinct rodent hindlimb muscles that have well characterized differences in energetic efficiency (locomotory- extensor digitorum longus (EDL) and postural- soleus muscles) following a 24 hour fasting period that resulted in substantially reduced muscle carbohydrate supply. 180 mins of acute hypoxia resulted in complete energetic failure in all muscles tested, indicated by: loss of force production, substantial reductions in total adenosine nucleotide pool intermediates, and increased adenosine nucleotide degradation product-inosine monophosphate (IMP). These changes occurred in the absence of apparent myofiber structural damage assessed histologically by both transverse section and whole mount. Fasting and the associated reduction of the available intracellular carbohydrate pool (~50% decrease in skeletal muscle) did not significantly alter the timing to muscle functional impairment or affect the overall force/work capacities of either muscle type. Fasting resulted in greater passive tension development in both muscle types, which may have implications for the design of pre-clinical studies involving optimal timing of reperfusion or administration of precision therapeutics.
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    Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle
    (Oxford University Press, 2023-03-21) Amorese, Adam J.; Minchew, Everett C.; Tarpey, Michael D.; Readyoff, Andrew T.; Williamson, Nicholas C.; Schmidt, Cameron A.; McMillin, Shawna L.; Goldberg, Emma J.; Terwilliger, Zoe S.; Spangenburg, Quincy A.; Witczak, Carol A.; Brault, Jeffrey J.; Abel, E. Dale; McClung, Joseph M.; Fisher-Wellman, Kelsey H.; Spangenburg, Espen E.; Anatomy, Cell Biology and Physiology, School of Medicine
    The various functions of skeletal muscle (movement, respiration, thermogenesis, etc.) require the presence of oxygen (O2). Inadequate O2 bioavailability (ie, hypoxia) is detrimental to muscle function and, in chronic cases, can result in muscle wasting. Current therapeutic interventions have proven largely ineffective to rescue skeletal muscle from hypoxic damage. However, our lab has identified a mammalian skeletal muscle that maintains proper physiological function in an environment depleted of O2. Using mouse models of in vivo hindlimb ischemia and ex vivo anoxia exposure, we observed the preservation of force production in the flexor digitorum brevis (FDB), while in contrast the extensor digitorum longus (EDL) and soleus muscles suffered loss of force output. Unlike other muscles, we found that the FDB phenotype is not dependent on mitochondria, which partially explains the hypoxia resistance. Muscle proteomes were interrogated using a discovery-based approach, which identified significantly greater expression of the transmembrane glucose transporter GLUT1 in the FDB as compared to the EDL and soleus. Through loss-and-gain-of-function approaches, we determined that GLUT1 is necessary for the FDB to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage. Collectively, the data demonstrate that the FDB is uniquely resistant to hypoxic insults. Defining the mechanisms that explain the phenotype may provide insight towards developing approaches for preventing hypoxia-induced tissue damage.
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    Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms
    (Wiley, 2018) O'Rourke, Allison R.; Lindsay, Angus; Tarpey, Michael D.; Yuen, Samantha; McCourt, Preston; Nelson, D'anna M.; Perrin, Benjamin J.; Thomas, David D.; Spangenburg, Espen E.; Lowe, Dawn A.; Ervasti, James M.; Biology, School of Science
    While α-actin isoforms predominate in adult striated muscle, skeletal muscle-specific knockouts (KOs) of nonmuscle cytoplasmic βcyto- or γcyto-actin each cause a mild, but progressive myopathy effected by an unknown mechanism. Using transmission electron microscopy, we identified morphological abnormalities in both the mitochondria and the sarcoplasmic reticulum (SR) in aged muscle-specific βcyto- and γcyto-actin KO mice. We found βcyto- and γcyto-actin proteins to be enriched in isolated mitochondrial-associated membrane preparations, which represent the interface between mitochondria and sarco-endoplasmic reticulum important in signaling and mitochondrial dynamics. We also measured significantly elongated and interconnected mitochondrial morphologies associated with a significant decrease in mitochondrial fission events in primary mouse embryonic fibroblasts lacking βcyto- and/or γcyto-actin. Interestingly, mitochondrial respiration in muscle was not measurably affected as oxygen consumption was similar in skeletal muscle fibers from 12 month-old muscle-specific βcyto- and γcyto-actin KO mice. Instead, we found that the maximal rate of relaxation after isometric contraction was significantly slowed in muscles of 12-month-old βcyto- and γcyto-actin muscle-specific KO mice. Our data suggest that impaired Ca2+ re-uptake may presage development of the observed SR morphological changes in aged mice while providing a potential pathological mechanism for the observed myopathy.