CD34 regulates the skeletal muscle response to hypoxia
Chronic obstructive pulmonary disease (COPD) can sometimes be associated with skeletal muscle atrophy. Hypoxemic episodes, which occur during disease exacerbation and daily physical activity, are frequent in COPD patients. However, the link between hypoxemia and muscle atrophy remains unclear, along with mechanisms of muscle hypoxic stress response. Myogenic progenitors (MPs) and fibro/adipogenic progenitors (FAPs) express CD34 and participate to muscle mass maintenance. Although there is evidence linking CD34 expression and muscle repair, the link between CD34 expression, muscle wasting and the hypoxic stress observed in COPD has never been studied. Using a 2-day model of exposure to hypoxic conditions, we investigated the impact of hypoxia on skeletal muscle wasting and function, and elucidated the importance of CD34 expression in that response. A 2-day exposure to hypoxic conditions induces muscle atrophy, which was significantly worse in Cd34−/− mice compared to wild type (WT). Moreover, the lack of CD34 expression negatively impacts the maximal strength of the extensor digitorum longus muscle in response to hypoxia. Following exposure to hypoxic conditions, FAPs (which support MPs differentiation and myogenesis) are significantly lower in Cd34−/− mice compared to WT animals while the expression of myogenic regulatory factors and degradation factors (Atrogin) are similar. CD34 expression is important in the maintenance of muscle mass and function in response to hypoxic stress. These results highlight a new potential role for CD34 in muscle mass maintenance in hypoxic stress such as observed in COPD.
KeywordsCD34 Skeletal muscle Hypoxic conditions MPs FAPs COPD Muscle atrophy
Funding was provided by Fondation de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec / Fondation JD Bégin.
- Contreras O, Rebolledo DL, Oyarzun JE, Olguin HC, Brandan E (2016) Connective tissue cells expressing fibro/adipogenic progenitor markers increase under chronic damage: relevance in fibroblast-myofibroblast differentiation and skeletal muscle fibrosis. Cell Tissue Res 364(3):647–660PubMedGoogle Scholar
- Elia M, Fuller NJ, Hardingham CR, Graves M, Screaton N, Dixon AK, Ward LC (2000) Modeling leg sections by bioelectrical impedance analysis, dual-energy X-ray absorptiometry, and anthropometry: assessing segmental muscle volume using magnetic resonance imaging as a reference. Ann N Y Acad Sci 904:298–305PubMedGoogle Scholar
- Favier FB, Costes F, Defour A, Bonnefoy R, Lefai E, Bauge S, Peinnequin A, Benoit H, Freyssenet D (2010) Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia. Am J Physiol Regul Integr Comp Physiol 298(6):R1659–R1666PubMedGoogle Scholar
- Fiore D, Judson RN, Low M, Lee S, Zhang E, Hopkins C, Xu P, Lenzi A, Rossi FMV, Lemos DR (2016) Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration. Stem Cell Res 17(1):161–169PubMedGoogle Scholar
- Fry CS, Johnson DL, Ireland ML, Noehren B (2016) ACL injury reduces satellite cell abundance and promotes fibrogenic cell expansion within skeletal muscle. J Orthop Res 35:1876–1885Google Scholar
- Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigare R, Dekhuijzen PNR, Franssen F, Gayan-Ramirez G, Gea J, Gosker HR, Gosselink R, Hayot M, Hussain SNA, Janssens W (2014) An Official American Thoracic Society/European Respiratory Society Statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease executive summary. Am J Respir Crit Care Med 189(9):1121–1137Google Scholar
- Saccone V, Consalvi S, Giordani L, Mozzetta C, Barozzi I, Sandona M, Ryan T, Rojas-Munoz A, Madaro L, Fasanaro P, Borsellino G, De Bardi M, Frige G, Termanini A, Sun X, Rossant J, Bruneau BG, Mercola M, Minucci S, Puri PL (2014) HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Genes Dev 28(8):841–857PubMedPubMedCentralGoogle Scholar
- Watt MJ, Cheng Y (2017) Triglyceride metabolism in exercising muscle. Biochim Biophys Acta S1388–1981(17):30111–30119Google Scholar