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• W2150887242 abstract "Sickle cell anemia (SCA) is a hemoglobinopathy leading to major hematologic, hemorheologic, and hemodynamic disorders that induce various complications, including organ failure, and ultimately lead to death. Here, we assessed for the first time repercussions of SCA on skeletal muscle and its microvasculature. Twenty-seven sedentary Cameroonian volunteer men participated in the study. They were assigned to one of three groups according to their hemoglobin status (healthy control subjects, n = 10; sickle cell trait carriers, n = 10; and SCA patients, n = 7) and underwent muscle biopsy of the vastus lateralis. SCA was associated with microvessel rarefaction, decrease in capillary tortuosity, and widening of microvessel diameter. The absence of capillary wall reinforcement was shown by lack of wall thickening and lack of fibrous tissue or smooth muscle in their constitution. We also observed changes in fiber type distribution, muscle atrophy, an increase in satellite cell number, and a decrease in activity of creatine kinase and several oxidative enzymes. No signs of tissue necrosis, inflammatory stress, fibrosis, or segmented fibers were observed. The present study highlighted marked effects of SCA on microvascular, structural, and energetic characteristics of skeletal muscle. Sickle cell anemia (SCA) is a hemoglobinopathy leading to major hematologic, hemorheologic, and hemodynamic disorders that induce various complications, including organ failure, and ultimately lead to death. Here, we assessed for the first time repercussions of SCA on skeletal muscle and its microvasculature. Twenty-seven sedentary Cameroonian volunteer men participated in the study. They were assigned to one of three groups according to their hemoglobin status (healthy control subjects, n = 10; sickle cell trait carriers, n = 10; and SCA patients, n = 7) and underwent muscle biopsy of the vastus lateralis. SCA was associated with microvessel rarefaction, decrease in capillary tortuosity, and widening of microvessel diameter. The absence of capillary wall reinforcement was shown by lack of wall thickening and lack of fibrous tissue or smooth muscle in their constitution. We also observed changes in fiber type distribution, muscle atrophy, an increase in satellite cell number, and a decrease in activity of creatine kinase and several oxidative enzymes. No signs of tissue necrosis, inflammatory stress, fibrosis, or segmented fibers were observed. The present study highlighted marked effects of SCA on microvascular, structural, and energetic characteristics of skeletal muscle. Sickle cell anemia (SCA) is a genetic hemoglobinopathy leading to synthesis of abnormal hemoglobin (Hb)S. In its deoxygenated form, the mutated hemoglobin polymerizes, giving the red blood cells their particular sickle shape. Because hemolysis related to the fragility of the sickled erythrocytes is not compensated by erythropoiesis, the first clinical manifestation of the disease is severe hemolytic anemia. Sickled red blood cells also display a loss of deformability and an abnormal adhesion to the endothelium that favor the entrapment of erythrocytes in the microvasculature, resulting in vaso-occlusive crises1Serjeant G. Sickle Cell Disease.ed 2. Oxford University Press, Oxford1992Google Scholar and infarction of vital organs. Resolution of vaso-occlusive episodes amplifies inflammation2Nath K.A. Grande J.P. Croatt A.J. Frank E. Caplice N.M. Hebbel R.P. Katusic Z.S. Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury.Am J Pathol. 2005; 166: 963-972Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 3Gute D.C. Ishida T. Yarimizu K. Korthuis R.J. Inflammatory responses to ischemia and reperfusion in skeletal muscle.Mol Cell Biochem. 1998; 179: 169-187Crossref PubMed Scopus (218) Google Scholar, 4Carden D.L. Granger D.N. Pathophysiology of ischaemia-reperfusion injury.J Pathol. 2000; 190: 255-266Crossref PubMed Scopus (1415) Google Scholar, 5Eltzschig H.K. Eckle T. Ischemia and reperfusion–from mechanism to translation.Nat Med. 2011; 17: 1391-1401Crossref PubMed Scopus (2104) Google Scholar and oxidative stress4Carden D.L. Granger D.N. Pathophysiology of ischaemia-reperfusion injury.J Pathol. 2000; 190: 255-266Crossref PubMed Scopus (1415) Google Scholar, 6Chirico E.N. Pialoux V. Role of oxidative stress in the pathogenesis of sickle cell disease.IUBMB Life. 2012; 64: 72-80Crossref PubMed Scopus (144) Google Scholar that contribute to the pathophysiology of SCA and especially vasculopathy. These vaso-occlusive or vasculopathic phenotypes often result in failure of critical organs such as the spleen, kidneys, liver, brain, lungs, and bones.7Gladwin M.T. Sachdev V. Cardiovascular abnormalities in sickle cell disease.J Am Coll Cardiol. 2012; 59: 1123-1133Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Literature related to skeletal muscle in SCA is relatively sparse, maybe because of its less vital nature, but also because sickle myonecrosis episodes are relatively rare complications.8Vicari P. Choairy A.C. Siufi G.C. Arantes A.M. Fonseca J.R. Figueiredo M.S. Embolization of intracranial aneurysms and sickle cell disease.Am J Hematol. 2004; 76: 83-84Crossref PubMed Scopus (19) Google Scholar, 9Valeriano-Marcet J. Kerr L.D. Myonecrosis and myofibrosis as complications of sickle cell anemia.Ann Intern Med. 1991; 115: 99-101Crossref PubMed Scopus (23) Google Scholar, 10Schumacher Jr., H.R. Murray W.M. Dalinka M.K. Acute muscle injury complicating sickle cell crisis.Semin Arthritis Rheum. 1990; 19: 243-247Abstract Full Text PDF PubMed Scopus (15) Google Scholar, 11Mani S. Duffy T.P. Sickle myonecrosis revisited.Am J Med. 1993; 95: 525-530Abstract Full Text PDF PubMed Scopus (22) Google Scholar, 12Malekgoudarzi B. Feffer S. Myonecrosis in sickle cell anemia.N Engl J Med. 1999; 340: 483Crossref PubMed Google Scholar However, richly microvascularized and sensitive to hypoxia and anoxia, oxidative stress, and inflammation, skeletal muscle may sustain severe damage from the disease. Occlusion and ischemia-reperfusion episodes are known to induce profound microvascular functional and structural remodeling, including alterations of capillary perfusion4Carden D.L. Granger D.N. Pathophysiology of ischaemia-reperfusion injury.J Pathol. 2000; 190: 255-266Crossref PubMed Scopus (1415) Google Scholar (no reflow phenomena3Gute D.C. Ishida T. Yarimizu K. Korthuis R.J. Inflammatory responses to ischemia and reperfusion in skeletal muscle.Mol Cell Biochem. 1998; 179: 169-187Crossref PubMed Scopus (218) Google Scholar, 5Eltzschig H.K. Eckle T. Ischemia and reperfusion–from mechanism to translation.Nat Med. 2011; 17: 1391-1401Crossref PubMed Scopus (2104) Google Scholar) and a decrease in capillary density.13Kawada S. Ishii N. Changes in skeletal muscle size, fibre-type composition and capillary supply after chronic venous occlusion in rats.Acta Physiol (Oxf). 2008; 192: 541-549Crossref PubMed Scopus (23) Google Scholar Hypoxemia related to anemia and arterial oxyhemoglobin desaturation14Setty B.N. Stuart M.J. Dampier C. Brodecki D. Allen J.L. Hypoxaemia in sickle cell disease: biomarker modulation and relevance to pathophysiology.Lancet. 2003; 362: 1450-1455Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 15Quinn C.T. Sargent J.W. Daytime steady-state haemoglobin desaturation is a risk factor for overt stroke in children with sickle cell anaemia.Br J Haematol. 2008; 140: 336-339Crossref PubMed Scopus (49) Google Scholar may induce chronic periods of tissular hypoxia, which has been reported ultimately to depress muscle oxidative capacity via tumor necrosis factor-α and NF-κB cascades.16Remels A.H. Gosker H.R. Schrauwen P. Hommelberg P.P. Sliwinski P. Polkey M. Galdiz J. Wouters E.F. Langen R.C. Schols A.M. TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?.FASEB J. 2010; 24: 5052-5062Crossref PubMed Scopus (102) Google Scholar, 17de Theije C. Costes F. Langen R.C. Pison C. Gosker H.R. Hypoxia and muscle maintenance regulation: implications for chronic respiratory disease.Curr Opin Clin Nutr Metab Care. 2011; 14: 548-553Crossref PubMed Scopus (29) Google Scholar Furthermore, reperfusion subsequent to ischemia also is known to induce alteration of muscle oxidative phenotype.16Remels A.H. Gosker H.R. Schrauwen P. Hommelberg P.P. Sliwinski P. Polkey M. Galdiz J. Wouters E.F. Langen R.C. Schols A.M. TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?.FASEB J. 2010; 24: 5052-5062Crossref PubMed Scopus (102) Google Scholar From these points of view, changes in muscle energetics can be assumed in patients with SCA. Moreover, ischemia and tissular anoxia related to vaso-occlusive crises potentially may lead to tissue necrosis,3Gute D.C. Ishida T. Yarimizu K. Korthuis R.J. Inflammatory responses to ischemia and reperfusion in skeletal muscle.Mol Cell Biochem. 1998; 179: 169-187Crossref PubMed Scopus (218) Google Scholar and the pro-inflammatory state2Nath K.A. Grande J.P. Croatt A.J. Frank E. Caplice N.M. Hebbel R.P. Katusic Z.S. Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury.Am J Pathol. 2005; 166: 963-972Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 3Gute D.C. Ishida T. Yarimizu K. Korthuis R.J. Inflammatory responses to ischemia and reperfusion in skeletal muscle.Mol Cell Biochem. 1998; 179: 169-187Crossref PubMed Scopus (218) Google Scholar, 4Carden D.L. Granger D.N. Pathophysiology of ischaemia-reperfusion injury.J Pathol. 2000; 190: 255-266Crossref PubMed Scopus (1415) Google Scholar, 5Eltzschig H.K. Eckle T. Ischemia and reperfusion–from mechanism to translation.Nat Med. 2011; 17: 1391-1401Crossref PubMed Scopus (2104) Google Scholar and oxidative stress4Carden D.L. Granger D.N. Pathophysiology of ischaemia-reperfusion injury.J Pathol. 2000; 190: 255-266Crossref PubMed Scopus (1415) Google Scholar, 6Chirico E.N. Pialoux V. Role of oxidative stress in the pathogenesis of sickle cell disease.IUBMB Life. 2012; 64: 72-80Crossref PubMed Scopus (144) Google Scholar related to reperfusion subsequent to ischemia also are known to induce muscle atrophy18Kondo H. Miura M. Itokawa Y. Oxidative stress in skeletal muscle atrophied by immobilization.Acta Physiol Scand. 1991; 142: 527-528Crossref PubMed Scopus (121) Google Scholar, 19Powers S.K. Jackson M.J. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production.Physiol Rev. 2008; 88: 1243-1276Crossref PubMed Scopus (1604) Google Scholar and possibly necrosis.3Gute D.C. Ishida T. Yarimizu K. Korthuis R.J. Inflammatory responses to ischemia and reperfusion in skeletal muscle.Mol Cell Biochem. 1998; 179: 169-187Crossref PubMed Scopus (218) Google Scholar, 20Ejindu V.C. Hine A.L. Mashayekhi M. Shorvon P.J. Misra R.R. Musculoskeletal manifestations of sickle cell disease.Radiographics. 2007; 27: 1005-1021Crossref PubMed Scopus (111) Google Scholar Therefore, even if myonecrosis is not a leading component of sickle crisis,11Mani S. Duffy T.P. Sickle myonecrosis revisited.Am J Med. 1993; 95: 525-530Abstract Full Text PDF PubMed Scopus (22) Google Scholar the major hematologic, hemorheologic, and hemodynamic disorders associated with SCA could lead to a profound remodeling of skeletal muscle and its microvasculature, which could worsen patients’ morbidity and loss of autonomy. Because of the lack of knowledge of muscular repercussions of SCA, we studied microvascular, structural, anatomopathological, and energetic characteristics of skeletal muscle in homozygous patients, heterozygous carriers, and control subjects. Twenty-seven sedentary Cameroonian men [healthy control (CON) subjects, n = 10; sickle cell trait (SCT) carriers, n = 10; and SCA patients, n = 7] participated in this study (Table 1), which took place at the Yaoundé General Hospital (Cameroon). The experiment was approved by the ethics committee (no. 02–06–2007) and conformed to the standards set by the Declaration of Helsinki for human studies. Before giving their written consent, eligible volunteers were informed fully of the objectives, procedures, and possible risks and discomforts related to the protocol.Table 1Anthropometric, Hemoglobinic, and Hematologic Data of the ParticipantsCharacteristicCON, n = 10SCT, n = 10SCA, n = 7Anthropometric data Age, years25 ± 123 ± 124 ± 2 Height, cm176 ± 2176 ± 1171 ± 3 Body mass, kg72 ± 268 ± 259 ± 3∗P < 0.01, ∗∗∗P < 0.001 versus CON.†P < 0.05, †††P < 0.001 versus SCT. Body fat, %13 ± 111 ± 111 ± 1 Body mass index, kg/m223.1 ± 0.621.9 ± 0.420.6 ± 0.8P < 0.01, ∗∗∗P < 0.001 versus CON.Hemoglobinic and hematological data HbS, %31.65 ± 1.89∗P < 0.01, ∗∗∗P < 0.001 versus CON.80.90 ± 2.02∗P < 0.01, ∗∗∗P < 0.001 versus CON.†P < 0.05, †††P < 0.001 versus SCT. HbF, %0.08 ± 0.084.63 ± 1.36∗P < 0.01, ∗∗∗P < 0.001 versus CON.†P < 0.05, †††P < 0.001 versus SCT. Hb, g/dL14.1 ± 0.313.4 ± 0.38.8 ± 0.6∗P < 0.01, ∗∗∗P < 0.001 versus CON.†P < 0.05, †††P < 0.001 versus SCT. Hct, %41.1 ± 0.839.8 ± 0.625.2 ± 1.9∗P < 0.01, ∗∗∗P < 0.001 versus CON.†P < 0.05, †††P < 0.001 versus SCT.Data are expressed as means ± SEM.CON, healthy control; Hb, hemoglobin total; HbF, fetal hemoglobin; HbS, hemoglobin S; Hct, hematocrit; SCA, sickle cell anemia; SCT, sickle cell trait.∗∗ P < 0.01, ∗∗∗P < 0.001 versus CON.† P < 0.05, †††P < 0.001 versus SCT. Open table in a new tab Data are expressed as means ± SEM. CON, healthy control; Hb, hemoglobin total; HbF, fetal hemoglobin; HbS, hemoglobin S; Hct, hematocrit; SCA, sickle cell anemia; SCT, sickle cell trait. All subjects underwent preliminary screening, including a physical examination and a blood phenotype analysis (Table 1). Volunteers who i) had had a malaria episode within the previous two months; ii) had more than three vaso-occlusive crises per year that required hospitalization ie, displayed a severe clinical phenotype21Platt O.S. Thorington B.D. Brambilla D.J. Milner P.F. Rosse W.F. Vichinsky E. Kinney T.R. Pain in sickle cell disease. Rates and risk factors.N Engl J Med. 1991; 325: 11-16Crossref PubMed Scopus (1245) Google Scholar; iii) took any medications; iv) tested positive for HIV; or v) were taking part in another research program were not included in the study. Subjects arrived at the hospital at either 8 AM or noon. Muscle biopsy of the right vastus lateralis was performed percutaneously.22Féasson L. Stockholm D. Freyssenet D. Richard I. Duguez S. Beckmann J.S. Denis C. Molecular adaptations of neuromuscular disease-associated proteins in response to eccentric exercise in human skeletal muscle.J Physiol. 2002; 543: 297-306Crossref PubMed Scopus (182) Google Scholar After the patient was shaved, asepsis was attained using alcohol and iso-Betadine 10% (MEDA Pharma, Paris, France), and local anesthesia of cutaneous and subcutaneous tissues was attained (2% lidocaine; AstraZeneca, Rueil-Malmaison, France), without crossing the muscular aponeurosis. A small incision was made until the crossing of the epimysium, through which a Weil-Blakesley forceps (Lawton, Tuttlingen, Germany) was introduced and the sample extracted (approximately 100 to 150 mg). Part of the biopsy sample was mounted in Cryomount (Histolab, Göteborg, Sweden), then frozen in isopentane (Chevron Phillips Chemicals International, Overijse, Belgium), and finally stored in liquid nitrogen until histochemical and immunohistochemical analyses were performed on 10-μm thick serial cryostat transverse sections. The remainder of the sample (frozen and stored in liquid nitrogen) was devoted to enzyme activity analyses. Morphometric analysis of microvasculature was performed as done previously.23Vincent L. Féasson L. Oyono-Enguéllé S. Banimbek V. Denis C. Guarneri C. Aufradet E. Monchanin G. Martin C. Gozal D. Dohbobga M. Wouassi D. Garet M. Thiriet P. Messonnier L. Remodeling of skeletal muscle microvasculature in sickle cell trait and alpha-thalassemia.Am J Physiol Heart Circ Physiol. 2010; 298: H375-H384Crossref PubMed Scopus (33) Google Scholar Briefly, capillaries were identified with CD31 antibody (Dako, Glostrup, Denmark), which recognizes platelet endothelial cell adhesion molecule 1, expressed by vascular endothelial cells. Capillary wall thickness was measured with hematoxylin-eosin-safran staining. The presence of smooth muscle myosin heavy chain and fibrous or collagenous tissue was determined by means of immunofluorescence (double staining CD31 and smooth muscle myosin heavy chain, Abcam, Cambridge, UK) and Van Gieson staining,24Dubowitz V. Sewry C.A. Lane R. Muscle Biopsy: A Practical Approach. 3rd ed. Saunders Elsevier, Philadelphia2007Google Scholar respectively. Fiber type determination, distribution, and morphology were analyzed as previously described.25Vincent L. Féasson L. Oyono-Enguéllé S. Banimbek V. Monchanin G. Dohbobga M. Wouassi D. Martin C. Gozal D. Geyssant A. Thiriet P. Denis C. Messonnier L. Skeletal muscle structural and energetic characteristics in subjects with sickle cell trait, alpha-thalassemia, or dual hemoglobinopathy.J Appl Physiol (1985). 2010; 109: 728-734Crossref PubMed Scopus (16) Google Scholar Fiber type was determined on immunohistochemical preparations by using anti-fast IIa myosin heavy chain N2.261 (Alexis Biochemicals, San Diego, CA) and anti-slow myosin heavy chain A4.951 (Alexis Biochemicals) monoclonal antibodies. The fiber types were designated as I, I-IIa, IIa, IIa-IIx, and IIx (previously referred to as IIb by Brooke and Kaiser26Brooke M.H. Kaiser K.K. Muscle fiber types: how many and what kind?.Arch Neurol. 1970; 23: 369-379Crossref PubMed Scopus (1834) Google Scholar).25Vincent L. Féasson L. Oyono-Enguéllé S. Banimbek V. Monchanin G. Dohbobga M. Wouassi D. Martin C. Gozal D. Geyssant A. Thiriet P. Denis C. Messonnier L. Skeletal muscle structural and energetic characteristics in subjects with sickle cell trait, alpha-thalassemia, or dual hemoglobinopathy.J Appl Physiol (1985). 2010; 109: 728-734Crossref PubMed Scopus (16) Google Scholar, 27Verney J. Kadi F. Charifi N. Féasson L. Saafi M.A. Castells J. Piehl-Aulin K. Denis C. Effects of combined lower body endurance and upper body resistance training on the satellite cell pool in elderly subjects.Muscle Nerve. 2008; 38: 1147-1154Crossref PubMed Scopus (115) Google Scholar Hematoxylin-eosin-safran staining enabled evaluation of common muscle remodeling signs such as necrotic fibers, fibrosis, fat cells, inflammation signs, internalized nuclei, and segmented fibers. Major histocompatibility complex I also was used to look for inflammation.24Dubowitz V. Sewry C.A. Lane R. Muscle Biopsy: A Practical Approach. 3rd ed. Saunders Elsevier, Philadelphia2007Google Scholar Counts of regenerated fibers and neofibers and satellite cells were performed using monoclonal antibody CD56 (Dako) with Mayer hematoxylin counterstaining allowing visualization of nuclei.28Kadi F. Schjerling P. Andersen L.L. Charifi N. Madsen J.L. Christensen L.R. Andersen J.L. The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles.J Physiol. 2004; 558: 1005-1012Crossref PubMed Scopus (255) Google Scholar Creatine kinase, phosphofructokinase, lactate dehydrogenase, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase activities were measured at 25°C. Cytochrome c oxidase (COX) assessment per fiber type was performed as previously described using SigmaScan Pro (SPSS, Chicago, IL).25Vincent L. Féasson L. Oyono-Enguéllé S. Banimbek V. Monchanin G. Dohbobga M. Wouassi D. Martin C. Gozal D. Geyssant A. Thiriet P. Denis C. Messonnier L. Skeletal muscle structural and energetic characteristics in subjects with sickle cell trait, alpha-thalassemia, or dual hemoglobinopathy.J Appl Physiol (1985). 2010; 109: 728-734Crossref PubMed Scopus (16) Google Scholar Optical density for each muscle fiber was determined using SigmaScan Pro to measure COX intensity. For each subject, a single value per fiber type was obtained by averaging measurements from approximately 60 well-identified muscle fibers. Muscle sections were viewed and analyzed under a light microscope (DM2000; Leica Microsystems, Wetzlar, Germany) connected to a digital camera (DFC490, Leica). Images were analyzed by an investigator (M.R.) blinded to the nature of the samples by using SigmaScan Pro.23Vincent L. Féasson L. Oyono-Enguéllé S. Banimbek V. Denis C. Guarneri C. Aufradet E. Monchanin G. Martin C. Gozal D. Dohbobga M. Wouassi D. Garet M. Thiriet P. Messonnier L. Remodeling of skeletal muscle microvasculature in sickle cell trait and alpha-thalassemia.Am J Physiol Heart Circ Physiol. 2010; 298: H375-H384Crossref PubMed Scopus (33) Google Scholar, 25Vincent L. Féasson L. Oyono-Enguéllé S. Banimbek V. Monchanin G. Dohbobga M. Wouassi D. Martin C. Gozal D. Geyssant A. Thiriet P. Denis C. Messonnier L. Skeletal muscle structural and energetic characteristics in subjects with sickle cell trait, alpha-thalassemia, or dual hemoglobinopathy.J Appl Physiol (1985). 2010; 109: 728-734Crossref PubMed Scopus (16) Google Scholar Descriptive statistics are expressed as means ± SEM. When the one-way analysis of variance revealed an HbS effect (see Results), Fisher post hoc tests were used to compare the three groups (see Results). Differences were considered to be significant for P < 0.05 and to represent a tendency for 0.05 ≤ P < 0.1. SCA was associated with decreased capillary density (P = 0.0012) (Figure 1A) and number of capillaries in contact with a fiber (P < 0.0001) (Table 2). The estimated blood volume in the 10-μm slice was unaffected by HbS (Table 2), which is due to the increase of the capillary surface area in patients (P = 0.0009) (Table 2). Capillary tortuosity was lower in SCA patients (P < 0.0001) (Figure 1B), whereas the length of capillaries in contact with a fiber over the perimeter of the fiber was not affected (Table 2). Capillary outer diameter increased strikingly with HbS (P < 0.0001) (Figure 2A) so that the percentage (Figure 2B) and number (Figure 2C) of wide microvessels (>10 μm) increased (P < 0.0001 for both), whereas the percentage (Figure 2B) and number (Figure 2C) of narrow capillaries (<5 μm) decreased (P < 0.0001 and P = 0.0003, respectively) in SCT carriers and decreased further in SCA patients compared with CON subjects.Table 2Microvascular Remodeling in Healthy Control, Sickle Cell Anemia, and Sickle Cell Trait MuscleMicrovascular characteristicCON, n = 10SCT, n = 10SCA, n = 7Number of capillaries per fiber4.68 ± 0.214.15 ± 0.222.53 ± 0.11∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.†P <0.05, ††P < 0.01, and †††P < 0.001 versus SCT.Capillary surface area, μm245.6 ± 2.543.2 ± 1.865.4 ± 7.0P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.†P <0.05, ††P < 0.01, and †††P < 0.001 versus SCT.CD × CSA‡CD × CSA: capillary density × capillary surface area, to estimate instantaneous blood volume in a 10-μm thick slice.15,573 ± 87813,897 ± 61618,010 ± 1590P <0.05, ††P < 0.01, and †††P < 0.001 versus SCT.LC/PF, %§LC/PF: length of capillaries in contact with a fiber over the perimeter of the fiber, to estimate the functional surface of exchange.14.49 ± 0.8213.50 ± 0.8615.88 ± 0.76Capillary wall thickness, μm0.50 ± 0.020.50 ± 0.020.44 ± 0.03Capillary wall thickness/COD, μm0.119 ± 0.0100.092 ± 0.006∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.0.061 ± 0.007∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.†P <0.05, ††P < 0.01, and †††P < 0.001 versus SCT.Values are means ± SEM.COD, capillary outer diameter; CON, healthy control; SCA, sickle cell anemia; SCT, sickle cell trait.∗ P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.† P <0.05, ††P < 0.01, and †††P < 0.001 versus SCT.‡ CD × CSA: capillary density × capillary surface area, to estimate instantaneous blood volume in a 10-μm thick slice.§ LC/PF: length of capillaries in contact with a fiber over the perimeter of the fiber, to estimate the functional surface of exchange. Open table in a new tab Figure 2Capillary outer diameter (COD). A: Mean COD. B: Percentage of capillaries with COD less than 5 μm, 5 to 10 μm, and greater than 10 μm. C: Number of capillaries with COD less than 5 μm, 5 to 10 μm, and greater than 10 μm. CON, healthy control; SCA, sickle cell anemia; SCT, sickle cell trait. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Values are means ± SEM. COD, capillary outer diameter; CON, healthy control; SCA, sickle cell anemia; SCT, sickle cell trait. Immunofluorescence [double staining endothelial cells (CD31) + smooth muscle (smooth muscle myosin heavy chain)] and histochemical (Van Gieson stain) analyses did not reveal the presence of either smooth muscle (Figure 3A) or fibrous or collagenous tissue (Figure 3B) around the studied capillaries. Microvessel wall thickness was not different among the three groups, but it tended to be thinner in patients than in carriers and CONs (P = 0.0813 and P = 0.0909, respectively) (Table 2). The ratio of capillary wall thickness over capillary outer diameter decreased as a function of HbS percentage (P = 0.0003) (Table 2). Percentage of type I fibers increased in patients (P = 0.0335), whereas percentages of type IIa and IIa-IIx fibers were lower (P = 0.0255 and P = 0.0482, respectively). No difference was found among the groups concerning distribution of type I-IIa and IIx fibers (Figure 4A). The mean surface areas of type I and IIa fibers decreased in patients (P = 0.0045 and P = 0.0029, respectively). Mean surface area of type IIx and hybrid (I-IIa and IIa-IIx) fibers did not differ among the groups (Figure 4B). Surface area for 100 myocytes (taking into account fiber type distribution) demonstrated clear amyotrophy in patients (P = 0.0130) (Figure 4C). In terms of degenerative signs, more interfascicular adipocytes were observed in patients (P = 0.0160). However, no differences were observed among the three groups in term of tissue necrosis and inflammatory infiltrate. Concerning regenerative signs, a higher number of internalized nuclei was found in carriers than in patients (P = 0.0193) and CONs (P = 0.0110), with no difference between the two latter groups. A higher number of satellite cells per 100 muscle fibers was found with HbS (P < 0.0001) (Table 3).Table 3Muscle Structural, Pathophysiological, and Energetic CharacteristicsSign or activityCON, n = 10SCT, n = 10SCA, n = 7Structural remodeling: degenerative signs Necrotic fibers‡Values are percentage of subjects showing histologic signs (number of subjects).0 (0)0 (0)0 (0) Lymphocytes, macrophages, MHC-I‡Values are percentage of subjects showing histologic signs (number of subjects).0 (0)0 (0)0 (0) Adipocytes‡Values are percentage of subjects showing histologic signs (number of subjects).10 (1)10 (1)57 (4) Fibrosis‡Values are percentage of subjects showing histologic signs (number of subjects).0 (0)10 (1)0 (0)Structural remodeling: regenerative signs Subjects with segmented fibers, %‡Values are percentage of subjects showing histologic signs (number of subjects).20 (2)50 (5)29 (2) Nuclei internalization, % myocytes§Values are expressed as means ± SEM.2.1 ± 0.65.0 ± 0.9∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.2.1 ± 0.8†P < 0.05, ††P < 0.01, and †††P < 0.001 versus SCT. Fibers CD56+, % myocytes§Values are expressed as means ± SEM.1.6 ± 0.81.3 ± 0.42.7 ± 0.9 Satellite cells, % myocytes§Values are expressed as means ± SEM.3.3 ± 0.55.2 ± 0.4P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.7.5 ± 0.2∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.P < 0.05, ††P < 0.01, and †††P < 0.001 versus SCT.Enzyme activities CK§Values are expressed as means ± SEM.1822 ± 361773 ± 501568 ± 90P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.†P < 0.05, ††P < 0.01, and †††P < 0.001 versus SCT. PFK§Values are expressed as means ± SEM.285.2 ± 9.6306.0 ± 13.5305.8 ± 11.3 LDH§Values are expressed as means ± SEM.852.2 ± 41.5897.5 ± 44.1794.3 ± 40.3 CS§Values are expressed as means ± SEM.20.7 ± 1.120.6 ± 0.814.2 ± 0.7∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.†P < 0.05, ††P < 0.01, and †††P < 0.001 versus SCT. β-HAD§Values are expressed as means ± SEM.17.6 ± 1.015.0 ± 0.7∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.12.3 ± 0.7∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.†P < 0.05, ††P < 0.01, and †††P < 0.001 versus SCT. COX type I§Values are expressed as means ± SEM.179 ± 3183 ± 2180 ± 4 COX type IIa§Values are expressed as means ± SEM.156 ± 3155 ± 4145 ± 3∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON. COX type IIx§Values are expressed as means ± SEM.134 ± 3123 ± 5∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.120 ± 3∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.For enzyme activities, values are expressed for all activities as μmol · min−1 · g−1 dry muscle except for COX activity, which is expressed in arbitrary units.β-HAD, β-hydroxyacyl-CoA dehydrogenase; CK, creatine kinase; CON, healthy control; COX, cytochrome c oxidase; CS, citrate synthase; LDH, lactate dehydrogenase; MHC-I, major histocompatibility complex I; PFK, phosphofructokinase; SCA, sickle cell anemia; SCT, sickle cell trait.∗ P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus CON.† P < 0.05, ††P < 0.01, and †††P < 0.001 versus SCT.‡ Values are percentage of subjects showing histologic signs (number of subjects).§ Values are expressed as means ± SEM. Open table in a new tab For enzyme activities, values are expressed for all activities as μmol · min−1 · g−1 dry muscle except for COX activity, which is expr" @default.
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• W2150887242 date "2015-05-01" @default.
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• W2150887242 title "Evidence for a Profound Remodeling of Skeletal Muscle and Its Microvasculature in Sickle Cell Anemia" @default.
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• W2150887242 doi "https://doi.org/10.1016/j.ajpath.2015.01.023" @default.
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