biostudies-literatureAmorese AJNIDDK NIH HHSNHLBI NIH HHSNational Institutes of HealthNIAMS NIH HHSzqad012https://www.ebi.ac.uk/biostudies/studies/S-EPMC10165545biostudies-literatureUnknown4(3)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 <i>in vivo</i> hindlimb ischemia and <i>ex vivo</i> 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.Function (Oxford, England)Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.PMC10165545R01 AR070200R61 AR078100R01 DK103562AR078100R01 AR066660AR066660R21 AR081593R21AR081593HL157659R01DK103562R01AR070200R01 HL157659Readyoff ATBrault JJMinchew ECMcMillin SLGoldberg EJAbel EDFisher-Wellman KHTarpey MDSpangenburg EEAmorese AJTerwilliger ZSSchmidt CAWitczak CAMcClung JMWilliamson NCSpangenburg QAfalseHypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.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 <i>in vivo</i> hindlimb ischemia and <i>ex vivo</i> 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.2023-01-01T00:00:00Z20232024-11-21T01:40:11.66Z2024-11-21T01:40:11.66ZS-EPMC101655453716849610.1093/function/zqad012