Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B

Progressive limb and girdle muscle atrophy leading to loss of ambulation is a hallmark of dysferlinopathies, which include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. However, animal models fail to fully reproduce the disease severity observed in humans, with dysferlin-null (Dysf−/−) mice exhibiting minor muscle damage and weakness without dramatic ambulatory dysfunction. As we have previously reported significant Dysf expression in blood vessels, we investigated the role of vascular function in development of muscle pathology by generating a Dysf-deficient mouse model with vascular disease. This was achieved by crossing Dysf−/− mice with ApoE−/− mice, which have high levels of nonHDL-associated cholesterol. Double-knockout Dysf−/−ApoE−/− mice exhibited severe ambulatory dysfunction by 11 months of age. In limb-girdle muscles, histology confirmed dramatic muscle wasting, fibrofatty replacement, and myofiber damage in Dysf−/−ApoE−/− mice without affecting the ratio of centrally nucleated myofibers. Although there were no major changes in ex vivo diaphragm and soleus muscle function, histological analyses revealed these muscles to be untouched by damage and remodelling. In all, these data suggest that cholesterol may be deleterious to dysferlinopathic muscle and lead to ambulatory dysfunction. Moreover, differences in plasma lipid handling between mice and humans could be a key factor affecting dysferlinopathy severity Progressive limb and girdle muscle atrophy leading to loss of ambulation is a hallmark of dysferlinopathies, which include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. However, animal models fail to fully reproduce the disease severity observed in humans, with dysferlin-null (Dysf−/−) mice exhibiting minor muscle damage and weakness without dramatic ambulatory dysfunction. As we have previously reported significant Dysf expression in blood vessels, we investigated the role of vascular function in development of muscle pathology by generating a Dysf-deficient mouse model with vascular disease. This was achieved by crossing Dysf−/− mice with ApoE−/− mice, which have high levels of nonHDL-associated cholesterol. Double-knockout Dysf−/−ApoE−/− mice exhibited severe ambulatory dysfunction by 11 months of age. In limb-girdle muscles, histology confirmed dramatic muscle wasting, fibrofatty replacement, and myofiber damage in Dysf−/−ApoE−/− mice without affecting the ratio of centrally nucleated myofibers. Although there were no major changes in ex vivo diaphragm and soleus muscle function, histological analyses revealed these muscles to be untouched by damage and remodelling. In all, these data suggest that cholesterol may be deleterious to dysferlinopathic muscle and lead to ambulatory dysfunction. Moreover, differences in plasma lipid handling between mice and humans could be a key factor affecting dysferlinopathy severity Dysferlinopathies represent a class of inherited muscle disorders caused by mutations in the dysferlin (Dysf) gene (1.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Defective membrane repair in dysferlin-deficient muscular dystrophy.Nature. 2003; 423: 168-172Crossref PubMed Scopus (768) Google Scholar). These include limb-girdle muscular dystrophy (MD) type 2B (LGMD2B), Miyoshi myopathy, and distal anterior compartment myopathy, which all lead to progressive muscle wasting of limb and girdle muscles with significant or complete loss of ambulatory function (2.Urtizberea J.A. Bassez G. Leturcq F. Nguyen K. Krahn M. Levy N. Dysferlinopathies.Neurol. India. 2008; 56: 289-297Crossref PubMed Scopus (59) Google Scholar). Mechanistic evidence suggests that loss of normal Dysf expression results in insufficient repair of the plasma membrane due to blunted lipid patch fusion and abnormal trafficking of transmembrane proteins (1.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Defective membrane repair in dysferlin-deficient muscular dystrophy.Nature. 2003; 423: 168-172Crossref PubMed Scopus (768) Google Scholar, 3.Sharma A. Yu C. Leung C. Trane A. Lau M. Utokaparch S. Shaheen F. Sheibani N. Bernatchez P. A new role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2196-2204Crossref PubMed Scopus (45) Google Scholar). This patch-dependent system of membrane repair is important in tissues undergoing constant stress and injury such as skeletal muscle myofibers (4.Han R. Bansal D. Miyake K. Muniz V.P. Weiss R.M. McNeil P.L. Campbell K.P. Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury.J. Clin. Invest. 2007; 117: 1805-1813Crossref PubMed Scopus (137) Google Scholar), where loss of expression leads to progressive muscle degeneration and inflammation, all of which are observed in LGMD2B and Myoshi myopathy patients (5.Cai C. Weisleder N. Ko J.K. Komazaki S. Sunada Y. Nishi M. Takeshima H. Ma J. Membrane repair defects in muscular dystrophy are linked to altered interaction between MG53, caveolin-3, and dysferlin.J. Biol. Chem. 2009; 284: 15894-15902Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 6.Cenacchi G. Fanin M. De Giorgi L.B. Angelini C. Ultrastructural changes in dysferlinopathy support defective membrane repair mechanism.J. Clin. Pathol. 2005; 58: 190-195Crossref PubMed Scopus (88) Google Scholar, 7.Han R. Rader E.P. Levy J.R. Bansal D. Campbell K.P. Dystrophin deficiency exacerbates skeletal muscle pathology in dysferlin-null mice.Skelet. Muscle. 2011; 1: 35Crossref PubMed Scopus (39) Google Scholar). However, there are still no effective and approved pharmacological treatments for dysferlinopathies. Compared with human LGMD2B, mouse models of dysferlinopathies exhibit only minor myofiber wasting observable on skeletal muscle histology and, although ambulatory function slowly declines, complete loss of walking ability is rarely observed (1.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Defective membrane repair in dysferlin-deficient muscular dystrophy.Nature. 2003; 423: 168-172Crossref PubMed Scopus (768) Google Scholar, 8.Millay D.P. Maillet M. Roche J.A. Sargent M.A. McNally E.M. Bloch R.J. Molkentin J.D. Genetic manipulation of dysferlin expression in skeletal muscle: novel insights into muscular dystrophy.Am. J. Pathol. 2009; 175: 1817-1823Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). Although reconstitution of Dysf expression specifically in skeletal muscle has led to improved muscle function and pathology (8.Millay D.P. Maillet M. Roche J.A. Sargent M.A. McNally E.M. Bloch R.J. Molkentin J.D. Genetic manipulation of dysferlin expression in skeletal muscle: novel insights into muscular dystrophy.Am. J. Pathol. 2009; 175: 1817-1823Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), reports of Dysf expression in nonskeletal muscle tissues, such as cardiac myocytes and inflammatory cells, paint a more complex picture of the disease (9.Kesari A. Fukuda M. Knoblach S. Bashir R. Nader G.A. Rao D. Nagaraju K. Hoffman E.P. Dysferlin deficiency shows compensatory induction of Rab27A/Slp2a that may contribute to inflammatory onset.Am. J. Pathol. 2008; 173: 1476-1487Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Previous research by our group has shown that loss of Dysf expression causes severe vascular abnormalities such as impaired angiogenesis and endothelial dysfunction (3.Sharma A. Yu C. Leung C. Trane A. Lau M. Utokaparch S. Shaheen F. Sheibani N. Bernatchez P. A new role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2196-2204Crossref PubMed Scopus (45) Google Scholar). This was shown to be the consequence of robust Dysf expression in vascular cells such as smooth muscle and especially endothelial cells. Notably, a two-hit vascular hypothesis was proposed to explain the severity of muscle wasting in other forms of MD, postulating that observed muscle damage arises from areas of anoxia and ischemia caused by blood vessel abnormalities (10.Miike T. Sugino S. Ohtani Y. Taku K. Yoshioka K. Vascular endothelial cell injury and platelet embolism in Duchenne muscular dystrophy at the preclinical stage.J. Neurol. Sci. 1987; 82: 67-80Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 11.Lombard J.H. Microcirculation in a mouse model of Duchenne muscular dystrophy: another blow to the vascular hypothesis?.J. Appl. Physiol. (1985). 2011; 110: 587-588Crossref PubMed Scopus (3) Google Scholar). Because evidence of ischemia was not found in MD patients or animal models, most assume that the numerous vascular abnormalities reported are a compensatory response rather than acting as primary contributors to muscle wasting and degeneration (11.Lombard J.H. Microcirculation in a mouse model of Duchenne muscular dystrophy: another blow to the vascular hypothesis?.J. Appl. Physiol. (1985). 2011; 110: 587-588Crossref PubMed Scopus (3) Google Scholar). Although evidence of vascular dysfunction in Dysf-deficient MD patients is limited, lipid analysis in LGMD2B muscle revealed a significant increase in triglyceride (TG) levels and decrease in linoleic acid levels compared with unaffected controls (12.Srivastava N.K. Yadav R. Mukherjee S. Pal L. Sinha N. Abnormal lipid metabolism in skeletal muscle tissue of patients with muscular dystrophy: In vitro, high-resolution NMR spectroscopy based observation in early phase of the disease.Magn. Reson. Imaging. 2017; 38: 163-173Crossref PubMed Scopus (29) Google Scholar). As others have reported abnormal plasma and muscle lipid metabolism in other forms of MD and elevated cholesterol levels correlated with muscle pathology severity in some MD patients (13.Hughes B.P. Lipid changes in Duchenne muscular dystrophy.J. Neurol. Neurosurg. Psychiatry. 1972; 35: 658-663Crossref PubMed Scopus (44) Google Scholar, 14.Temin P.A. Islamova I.B. Plasma lipids of patients with Duchenne's muscular dystrophy at different stages of the disease.Zh. Nevropatol. Psikhiatr. Im. S. S. Korsakova. 1983; 83: 1632-1636PubMed Google Scholar, 15.Srivastava N.K. Pradhan S. Mittal B. Gowda G.A. High resolution NMR based analysis of serum lipids in Duchenne muscular dystrophy patients and its possible diagnostic significance.NMR Biomed. 2010; 23: 13-22Crossref PubMed Scopus (40) Google Scholar), we challenged the dynamic interplay between blood vessels and MD muscle tissues by generating dysferlinopathic mice with elevated levels of “bad,”non HDL-associated cholesterol (HDLc) (i.e., VLDL, LDL, and IDL) known to accelerate vascular disease and atherosclerosis by inactivating their ApoE gene (16.Sharma A. Sellers S. Stefanovic N. Leung C. Tan S.M. Huet O. Granville D.J. Cooper M.E. de Haan J.B. Bernatchez P. Direct eNOS activation provides atheroprotection in diabetes-accelerated atherosclerosis.Diabetes. 2015; 64: 3937-3950Crossref PubMed Scopus (50) Google Scholar). To our surprise, Dysf−/−ApoE−/− mice show a significant reduction in stride length followed by complete loss of ambulatory function when on a in to the of Dysf−/− mice (1.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Defective membrane repair in dysferlin-deficient muscular dystrophy.Nature. 2003; 423: 168-172Crossref PubMed Scopus (768) Google Scholar). analyses revealed that loss of ApoE causes dramatic of muscle wasting ex vivo muscle function revealed no major changes in and data suggest that levels of could in complete loss of walking ability in Dysf−/− mice, leading to a more model of This for of plasma abnormalities in dysferlinopathies as a primary to muscle damage fibrofatty replacement, and ambulation dysfunction rather than a consequence of myofiber degeneration or of was approved by the and at the of were in the at the for on a and to and Dysf−/− mice were from the and a for than of the Dysf gene was confirmed in Dysf−/− mice the by and from the Campbell of a ApoE−/− mice were from the and of the ApoE gene was confirmed by the of Dysf−/−ApoE−/− mice and was achieved by Dysf−/− mice to ApoE−/− to These were to and were at of and by or from with no cholesterol or with lipids and cholesterol by or from with at of age. of was from of on from mice walking a length was as the between from the in which a mouse were not and stride length mouse was from of observable muscle wasting in the was from of of the where was as the of a to the and from the anterior of the to the most of the analysis was on muscles and for at in and were and in was on and muscle myofiber and were was of on a high resolution nucleated were on of cholesterol were as or in histological of inflammatory cells was histological was in a to and in with a muscles were in in in and at muscles were at at were with to lipids in muscle tissue the by A. L. A. of lipids by for the in and PubMed Scopus Google Scholar). To were for the by the blood was in cardiac of mice at at for at and plasma at Plasma were the system for levels of cholesterol high and were muscles were and to to a and to length in of with was and as a of the by were on mice with a system with a was and a and were and by into the were and by a in A was to left to and as as cardiac of cardiac and analyses were of at a was to the of were compared at a was was to for A of than was show data as and Dysf−/−ApoE−/− mice no ambulatory at the most model of the increase in plasma with ApoE gene and was confirmed by in cholesterol and in that were not different between ApoE−/− and Dysf−/−ApoE−/− Although plasma levels were in ApoE−/− mice, there was no significant between Dysf−/−ApoE−/− and Dysf−/− ApoE−/− and Dysf−/−ApoE−/− cholesterol levels than and Dysf−/− mice than ApoE−/− and Dysf−/−ApoE−/− a 11 of Dysf−/−ApoE−/− on a severe ambulation as complete loss of and Dysf−/− mice on a as as Dysf−/−ApoE−/− on a no of ambulatory dysfunction by 11 A in stride length to controls was observed in Dysf−/−ApoE−/− mice on a and the 11 was not observed in at or or in Dysf−/−ApoE−/− mice a significant reduction in was between Dysf−/−ApoE−/− mice and and Dysf−/− at 11 of without significant at of Dysf−/−ApoE−/− mice not reduction in observed in at 11 This suggests that the in in Dysf−/−ApoE−/− mice caused by the of and a the dysferlinopathy in the model and lead to complete loss of mice atrophy without significant on ex vivo muscle is in Dysf−/−ApoE−/− mice compared with all other at 11 as as Dysf−/−ApoE−/− mice on a as in of mice 11 months of on a a minor of diaphragm muscle was observed of Dysf−/−ApoE−/− diaphragm muscles no dramatic changes in soleus muscle in the diaphragm and soleus were unaffected by 11 months of on a Because Dysf−/−ApoE−/− mice exhibit severe ambulation we investigated the of their muscles muscle and muscle ex vivo This was at the 11 for all diaphragm and soleus muscles of their of and To our surprise, no changes were observed in soleus or diaphragm muscle and Dysf−/−ApoE−/− diaphragm muscles were found to muscle than other at 11 As the of ex vivo muscle function in the soleus and diaphragm not to the dramatic of ambulatory function muscle was by revealed no pathology in the soleus or diaphragm muscles and of soleus muscle and no evidence of muscle wasting or on a by 11 This suggests that of ambulatory function observed in Dysf−/−ApoE−/− mice is not due to primary of muscle and function when ex revealed normal muscle in all and muscles As minor wasting was in the of the muscle in Dysf−/− mice, severe of Dysf−/− damage and fibrofatty was in Dysf−/−ApoE−/− on and revealed significant reduction in of at 11 of in Dysf−/−ApoE−/− and Dysf−/− mice compared with and ApoE controls on and However, analysis of muscle revealed a increase in and a reduction in myofiber the muscle in Dysf−/−ApoE−/− compared with all other of mice on at 11 and was with In the most severe 11 Dysf−/−ApoE−/− mice a to than with of the to of the muscle loss of ApoE not the of in Dysf−/− mice at 11 on or wasting was not to as analysis of muscle of revealed a of pathology in the with a muscle in Dysf−/−ApoE−/− mice in to Dysf−/− mice, which was by Although muscle wasting and were between Dysf−/− and Dysf−/−ApoE−/− mice Dysf−/−ApoE−/− mice exhibited as as significant reduction in myofiber on and In muscle was with damage at 11 on damage in Dysf−/− tissue Dysf−/−ApoE−/− mice exhibited significant and loss of muscle anterior muscles a severe of pathology with Dysf−/−ApoE−/− mice exhibiting a significant increase in and reduction in myofiber compared with Dysf−/− mice with minor differences in at 11 months of on a and muscle analyses by a revealed vascular of inflammatory cell in muscle tissue which was found to be in Dysf−/−ApoE−/− compared with all other Moreover, we the of cholesterol in and Dysf−/−ApoE−/− cholesterol was not in tissues from other areas of muscle were observed in Dysf−/− and Dysf−/−ApoE−/− muscle at of which by 11 of was by fibrofatty and cholesterol. In of dramatic the of significant was confirmed for in Dysf−/−ApoE−/− which be in with in In to the lipid in these muscles, of lipid in areas Dysf−/−ApoE−/− muscle with observed in Dysf−/− muscle the significant increase in muscle damage in Dysf−/−ApoE−/− compared with Dysf−/− mice, the of was not different between Dysf-deficient in the and at 11 months of on a Although cardiac dysfunction is not observed in dysferlinopathic Dysf expression was reported in and some have shown minor changes in the cardiac function of Dysf-deficient mice by G.A. L. O. Dysferlin deficiency and the development of in a mouse model of limb-girdle muscular dystrophy J. Pathol. 2009; 175: Full Text Full Text PDF PubMed Scopus (41) Google Scholar). However, in vivo analysis no significant differences in cardiac function or in ventricular and the that although Dysf−/−ApoE−/− mice show of significant vascular no cardiac pathology was data support the that ApoE gene in with a which lead to skeletal muscle pathology in the Dysf−/− model of Dysf−/− model is known to exhibit muscle pathology compared with dysferlinopathic patients K. T. M. J. Dysferlin and animal models for Pathol. PubMed Scopus Google Scholar), the Dysf−/−ApoE−/− mice severe muscle wasting and as as the complete loss of ambulatory function in of the mice a we that model more human of Although Dysf-deficient mice significant lipid in some muscles J.R. T. J. S. T. Lipid in dysferlin-deficient J. Pathol. Full Text Full Text PDF PubMed Scopus (50) Google Scholar, M. R. G.A. P. and and J. Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar), the of by 11 in our Dysf−/−ApoE−/− muscles is more severe and more of human leading to dramatic which is a of LGMD2B This with a high of as ApoE not muscle in dysferlinopathic patients exhibit fibrofatty in limb-girdle muscles, and with and anterior muscles, and cardiac muscles are (2.Urtizberea J.A. Bassez G. Leturcq F. Nguyen K. Krahn M. Levy N. Dysferlinopathies.Neurol. India. 2008; 56: 289-297Crossref PubMed Scopus (59) Google Scholar). In our Dysf−/−ApoE−/− mice, a of muscle damage was diaphragm and soleus muscles with cardiac function unaffected by In a from our group found that elevated in Duchenne MD led to mouse muscle pathology with a muscle and more than at and affecting and diaphragm muscles more N. Sellers S. Bernatchez P. plasma lipid levels muscle pathology in the mouse model of Duchenne muscular Muscle. 2017; PubMed Scopus Google Scholar). This suggests that the of on muscle are complex and not muscle ischemia or severe muscle as elevated exacerbates muscle pathology based on the type of MD is important to that increase in levels in our Dysf−/−ApoE−/− model not the of muscles by loss of Dysf rather primary disease only limb and muscles are in dysferlinopathies is not differences in muscle K. G. R. R. R. Dysferlin in skeletal muscle a progressive Neurol. 2010; Google has our data suggest that the of vascular between different muscles, such as from endothelial skeletal of Dysf has shown to the MD of Dysf-deficient (8.Millay D.P. Maillet M. Roche J.A. Sargent M.A. McNally E.M. Bloch R.J. Molkentin J.D. Genetic manipulation of dysferlin expression in skeletal muscle: novel insights into muscular dystrophy.Am. J. Pathol. 2009; 175: 1817-1823Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), we and others have reported Dysf expression in cells, such as vascular smooth muscle and endothelial cells as as inflammatory cells, and that loss of Dysf expression causes vascular abnormalities (3.Sharma A. Yu C. Leung C. Trane A. Lau M. Utokaparch S. Shaheen F. Sheibani N. Bernatchez P. A new role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2196-2204Crossref PubMed Scopus (45) Google Scholar, A. J. J. T. analysis of lipid from human endothelial 2005; PubMed Scopus (39) Google Scholar). that the role that these vascular abnormalities in the development of muscle pathology was by generating Dysf−/− with plasma lipid with vascular disease. of muscle wasting we observed with of vascular and a new on the in MD (11.Lombard J.H. Microcirculation in a mouse model of Duchenne muscular dystrophy: another blow to the vascular hypothesis?.J. Appl. Physiol. (1985). 2011; 110: 587-588Crossref PubMed Scopus (3) Google Scholar). as a major in MD due to the of in MD muscle tissues, vascular abnormalities be in preclinical and animal models of other of MD muscle damage (10.Miike T. Sugino S. Ohtani Y. Taku K. Yoshioka K. Vascular endothelial cell injury and platelet embolism in Duchenne muscular dystrophy at the preclinical stage.J. Neurol. Sci. 1987; 82: 67-80Abstract Full Text PDF PubMed Scopus (43) Google Scholar, N. Sellers S. Bernatchez P. plasma lipid levels muscle pathology in the mouse model of Duchenne muscular Muscle. 2017; PubMed Scopus Google Scholar). In our the significant areas of inflammatory cell and blood vessels suggest that the endothelial is and that the of muscle damage and could be of vascular with a that Dysf expression is in and vessels S. R. J. B. R. G. T. A. M. is a new for blood vessels in Neurol. PubMed Scopus Google Scholar), our data support the that of vascular function in Dysf−/− muscles results in of plasma lipids into muscle the primary Dysf−/− muscle levels of Dysf−/− myofiber myofiber or changes in the muscle to be data show a between muscle disease severity and for Dysf−/−ApoE−/− mice on a exhibited levels and muscle pathology between Dysf−/−ApoE−/− on a In no significant to levels was that the major role in muscle pathology in our Because Dysf is known to with and is possible that and may have on blunted repair found in Dysf-deficient myofibers S. C. G. A. the of human to in membrane at PubMed Scopus Google Scholar, M.A. T. J. J. J.R. the of membrane Sci. 2005; PubMed Scopus Google Scholar, in 110: PubMed Scopus Google Scholar, M. A. by fusion and the of with 2005; 289-297Crossref PubMed Scopus Google Scholar). has shown to be a key in and where or of cholesterol from the plasma membrane lead to fusion M.A. T. J. J. J.R. the of membrane Sci. 2005; PubMed Scopus Google Scholar). that of cholesterol led to improved fusion and that cholesterol may a role in early myofiber M. A. by fusion and the of with 2005; 289-297Crossref PubMed Scopus Google Scholar). of of muscle tissue is a in stress in the muscle Previous have shown that stress is in Dysf-deficient muscle and in other forms of MD, and that in with muscle damage Yu Y. A. cells from mice have to Full Text Full Text PDF PubMed Scopus Google Scholar, M. role of in the of muscular dystrophy.J. Appl. Physiol. (1985). 2007; PubMed Scopus Google Scholar, damage in role of and Physiol. PubMed Scopus Google Scholar, J.R. T. stress and pathology in muscular on protein and J. PubMed Scopus Google Scholar). as are known to be in the of and vascular disease and stress in vascular 2010; PubMed Scopus Google Scholar), stress and injury may have a significant on muscle the other of Dysf-deficient myofibers may be by inflammatory cells, found in in Dysf−/−ApoE−/− cell could in of Dysf-deficient myofiber may muscle the of fibrofatty of areas of myofiber Although our model of dysferlinopathy shows to human pathology than other models of the there are some important to be when the lipid of ApoE−/− mice and dysferlinopathic Lipid abnormalities have observed in LGMD2B patients (12.Srivastava N.K. Yadav R. Mukherjee S. Pal L. Sinha N. Abnormal lipid metabolism in skeletal muscle tissue of patients with muscular dystrophy: In vitro, high-resolution NMR spectroscopy based observation in early phase of the disease.Magn. Reson. Imaging. 2017; 38: 163-173Crossref PubMed Scopus (29) Google Scholar), loss of ApoE causes a in and with a dramatic increase in and to levels rarely in humans J.A. J.R. N. of mice a gene by gene in Sci. PubMed Scopus Google Scholar). Moreover, although ApoE is in the for cholesterol in tissues such as tissue and C. activation by acting on the 2003; PubMed Scopus Google Scholar, D. T. R. C. G. M. J. H. A. in Thromb. Vasc. Biol. 2011; PubMed Scopus Google Scholar), which may lipid metabolism and inflammatory important is that to that found significant of function J. in dysferlinopathy animal Clin. Neurol. 2015; PubMed Scopus Google Scholar, N. R.J. T. T. S.S. T. J. muscular dystrophy and of in dysferlin-deficient 2017; Scopus Google and muscle function ex vivo early and progressive in dysferlin-deficient 2010; PubMed Scopus Google in other LGMD2B mouse models, we not significant reduction in length or muscle function in Dysf−/− This is due to the between Dysf-deficient or and the (Dysf−/−) model in all of which have different levels of Dysf expression in the muscle and exhibit some important differences K. T. M. J. Dysferlin and animal models for Pathol. PubMed Scopus Google Scholar, K. T. M. J. and of skeletal muscle in dysferlin-deficient and Pathol. 2010; PubMed Scopus Google Scholar). However, be that our ex vivo muscle function data with a of damage or in the soleus and other found significant areas of and damage in muscles that exhibited impaired function ex vivo J. in dysferlinopathy animal Clin. Neurol. 2015; PubMed Scopus Google Scholar, early and progressive in dysferlin-deficient 2010; PubMed Scopus Google Scholar), the differences between the models of dysferlinopathies. to for and the of with centrally nucleated dysferlin HDL-associated cholesterol limb-girdle muscular dystrophy 2B muscular dystrophy triglyceride

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.