Browsing by Author "Rasmussen, Blake B."

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    Biology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy
    (Elsevier, 2022) Ebert, Scott M.; Rasmussen, Blake B.; Judge, Andrew R.; Judge, Sarah M.; Larsson, Lars; Wek, Ronald C.; Anthony, Tracy G.; Marcotte, George R.; Miller, Matthew J.; Yorek, Mark A.; Vella, Adrian; Volpi, Elena; Stern, Jennifer I.; Strub, Matthew D.; Ryan, Zachary; Talley, John J.; Adams, Christopher M.; Biochemistry and Molecular Biology, School of Medicine
    Activating transcription factor 4 (ATF4) is a multifunctional transcription regulatory protein in the basic leucine zipper superfamily. ATF4 can be expressed in most if not all mammalian cell types, and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, or growth factors. Because ATF4 is involved in a wide range of biological processes, its roles in human health and disease are not yet fully understood. Much of our current knowledge about ATF4 comes from investigations in cultured cell models, where ATF4 was originally characterized and where further investigations continue to provide new insights. ATF4 is also an increasingly prominent topic of in vivo investigations in fully differentiated mammalian cell types, where our current understanding of ATF4 is less complete. Here, we review some important high-level concepts and questions concerning the basic biology of ATF4. We then discuss current knowledge and emerging questions about the in vivo role of ATF4 in one fully differentiated cell type, mammalian skeletal muscle fibers.
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    Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma
    (APS Journals, 2016-08-01) Ogunbileje, John O.; Porter, Craig; Herndon, David N.; Chao, Tony; Abdelrahman, Doaa R.; Papadimitriou, Anastasia; Chondronikola, Maria; Zimmers, Teresa A.; Reidy, Paul T.; Rasmussen, Blake B.; Sidossis, Labros S.; Surgery, School of Medicine
    Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stress, cytosolic protein degradation, and mitochondrial stress as a result of hypermetabolism contribute to muscle cachexia postburn. Patients (n = 14) with burns covering >30% of their total body surface area were studied. Controls (n = 13) were young healthy adults. We found that burn patients were profoundly hypermetabolic at both the skeletal muscle and systemic levels, indicating increased oxygen consumption by mitochondria. In skeletal muscle of burn patients, concurrent activation of mTORC1 signaling and elevation in the fractional synthetic rate paralleled increased levels of proteasomes and elevated fractional breakdown rate. Burn patients had greater levels of oxidative stress markers as well as higher expression of mtUPR-related genes and proteins, suggesting that burns increased mitochondrial stress and protein damage. Indeed, upregulation of cytoprotective genes suggests hypermetabolism-induced oxidative stress postburn. In parallel to mtUPR activation postburn, mitochondrial-specific proteases (LONP1 and CLPP) and mitochondrial translocases (TIM23, TIM17B, and TOM40) were upregulated, suggesting increased mitochondrial protein degradation and transport of preprotein, respectively. Our data demonstrate that proteolysis occurs in both the cytosolic and mitochondrial compartments of skeletal muscle in severely burned patients. Increased mitochondrial protein turnover may be associated with increased protein damage due to hypermetabolism-induced oxidative stress and activation of mtUPR. Our results suggest a novel role for the mitochondria in burn-induced cachexia.