Dysferlin deficiency alters lipid metabolism and remodels the skeletal muscle lipidome in mice

Defects in the gene coding for dysferlin, a membrane-associated protein, affect many tissues, including skeletal muscles, with a resultant myopathy called dysferlinopathy. Dysferlinopathy manifests postgrowth with a progressive loss of skeletal muscle function, early intramyocellular lipid accumulation, and a striking later replacement of selective muscles by adipocytes. To better understand the changes underpinning this disease, we assessed whole-body energy homeostasis, skeletal muscle fatty acid metabolism, lipolysis in adipose tissue, and the skeletal muscle lipidome using young adult dysferlin-deficient male BLAJ mice and age-matched C57Bl/6J WT mice. BLAJ mice had increased lean mass and reduced fat mass associated with increased physical activity and increased adipose tissue lipolysis. Skeletal muscle fatty acid metabolism was remodeled in BLAJ mice, characterized by a partitioning of fatty acids toward storage rather than oxidation. Lipidomic analysis identified marked changes in almost all lipid classes examined in the skeletal muscle of BLAJ mice, including sphingolipids, phospholipids, cholesterol, and most glycerolipids but, surprisingly, not triacylglycerol. These observations indicate that an early manifestation of dysferlin deficiency is the reprogramming of skeletal muscle and adipose tissue lipid metabolism, which is likely to contribute to the progressive adverse histopathology in dysferlinopathies. Defects in the gene coding for dysferlin, a membrane-associated protein, affect many tissues, including skeletal muscles, with a resultant myopathy called dysferlinopathy. Dysferlinopathy manifests postgrowth with a progressive loss of skeletal muscle function, early intramyocellular lipid accumulation, and a striking later replacement of selective muscles by adipocytes. To better understand the changes underpinning this disease, we assessed whole-body energy homeostasis, skeletal muscle fatty acid metabolism, lipolysis in adipose tissue, and the skeletal muscle lipidome using young adult dysferlin-deficient male BLAJ mice and age-matched C57Bl/6J WT mice. BLAJ mice had increased lean mass and reduced fat mass associated with increased physical activity and increased adipose tissue lipolysis. Skeletal muscle fatty acid metabolism was remodeled in BLAJ mice, characterized by a partitioning of fatty acids toward storage rather than oxidation. Lipidomic analysis identified marked changes in almost all lipid classes examined in the skeletal muscle of BLAJ mice, including sphingolipids, phospholipids, cholesterol, and most glycerolipids but, surprisingly, not triacylglycerol. These observations indicate that an early manifestation of dysferlin deficiency is the reprogramming of skeletal muscle and adipose tissue lipid metabolism, which is likely to contribute to the progressive adverse histopathology in dysferlinopathies. Dysferlinopathies are a group of autosomal recessive rare muscular dystrophies that result from mutations in the dysferlin gene, first described in 1998 (1.Bashir R. Britton S. Strachan T. Keers S. Vafiadaki E. Lako M. Richard I. Marchand S. Bourg N. Argov Z. et al.A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.Nat. Genet. 1998; 20: 37-42Crossref PubMed Scopus (557) Google Scholar), and characterized by the onset of muscle weakness and loss of function usually in the late teens and with slow progression (2.Harris E. Bladen C.L. Mayhew A. James M. Bettinson K. Moore U. Smith F.E. Rufibach L. Cnaan A. Bharucha-Goebel D.X. et al.The Clinical Outcome Study for dysferlinopathy: an international multicenter study.Neurol. Genet. 2016; 2: e89Crossref PubMed Scopus (53) Google Scholar). Dysferlinopathies include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, with the proximal and distal limb-girdle muscles being the main muscles affected (2.Harris E. Bladen C.L. Mayhew A. James M. Bettinson K. Moore U. Smith F.E. Rufibach L. Cnaan A. Bharucha-Goebel D.X. et al.The Clinical Outcome Study for dysferlinopathy: an international multicenter study.Neurol. Genet. 2016; 2: e89Crossref PubMed Scopus (53) Google Scholar, 3.Fanin M. Angelini C. Progress and challenges in diagnosis of dysferlinopathy.Muscle Nerve. 2016; 54: 821-835Crossref PubMed Scopus (47) Google Scholar, 4.Diaz-Manera J. Fernandez-Torron R. LLauger J. James M.K. Mayhew A. Smith F.E. Moore U.R. Blamire A.M. Carlier P.G. Rufibach L. et al.Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials.J. Neurol. Neurosurg. Psychiatry. 2018; 89: 1071-1081Crossref PubMed Scopus (61) Google Scholar). Mouse models of dysferlinopathy harboring dysferlin deficiency or deletion (5.Ho M. Post C.M. Donahue L.R. Lidov H.G.W. Bronson R.T. Goolsby H. Watkins S.C. Cox G.A. Brown R.H. Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency.Hum. Mol. Genet. 2004; 13: 1999-2010Crossref PubMed Scopus (157) Google Scholar, 6.Hornsey M.A. Laval S.H. Barresi R. Lochmuller H. Bushby K. Muscular dystrophy in dysferlin-deficient mouse models.Neuromuscul. Disord. 2013; 23: 377-387Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 7.Kobayashi K. Izawa T. Kuwamura M. Yamate J. The distribution and characterization of skeletal muscle lesions in dysferlin-deficient SJL and A/J mice.Exp. Toxicol. Pathol. 2010; 62: 509-517Crossref PubMed Scopus (26) Google Scholar, 8.Kobayashi K. Izawa T. Kuwamura M. Yamate J. Dysferlin and animal models for dysferlinopathy.J. Toxicol. Pathol. 2012; 25: 135-147Crossref PubMed Scopus (37) Google Scholar) consistently have a late onset of dystropathology, by about 8 months of age, with pronounced replacement of myofibers by adipocytes (9.Grounds M.D. Terrill J.R. Radley-Crabb H.G. Robertson T. Papadimitriou J. Spuler S. Shavlakadze T. Lipid accumulation in dysferlin-deficient muscles.Am. J. Pathol. 2014; 184: 1668-1676Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Dysferlin is a member of a large ferlin family of transmembrane proteins that are involved in protein vesicle trafficking and fusion (10.Lek A. Evesson F.J. Sutton R.B. North K.N. Cooper S.T. Ferlins: regulators of vesicle fusion for auditory neurotransmission, receptor trafficking and membrane repair.Traffic. 2012; 13: 185-194Crossref PubMed Scopus (98) Google Scholar), with dysferlin initially attracting attention due to its role in the resealing of experimentally K. S. R. membrane in dysferlin-deficient muscular PubMed Scopus Google Scholar, L. Brown R.H. Dysferlin in membrane trafficking and repair.Traffic. PubMed Scopus Google Scholar, R. Dysferlin and muscle membrane PubMed Scopus Google Scholar). Dysferlin is in of skeletal muscles and L. J. and in skeletal muscle and in PubMed Scopus Google Scholar), a role in M. R. G.A. et and and J. Pathol. 2014; 184: Full Text Full Text PDF PubMed Scopus Google Scholar), and to involved in related to L. J. C. R. L. Laval S. M. Barresi R. et with the in and skeletal Nerve. 2010; PubMed Scopus Google Scholar, A.M. for dysferlin PubMed Scopus Google Scholar, J. Evesson F.J. A. et and are in muscular dystrophy and to of the with Neurol. PubMed Scopus Google Scholar). Dysferlin is in skeletal myofibers is in many K. C. J. M.A. R. Britton S. Keers S. et is a membrane protein and is early in Mol. Genet. PubMed Scopus Google Scholar) and including adipocytes M. R.T. J. S. J. C. J.R. M. et analysis of the PubMed Scopus (26) Google Scholar), K. R. E. R. A. S. N. Dysferlin deficiency a for the onset of limb-girdle muscular dystrophy J. Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar), and A. C. C. A. M. S. N. role for the muscle protein dysferlin in and 2010; PubMed Scopus Google Scholar). striking of and mouse dysferlin-deficient muscles are the accumulation of many lipid myofibers a later age, the replacement of myofibers with adipocytes (9.Grounds M.D. Terrill J.R. Radley-Crabb H.G. Robertson T. Papadimitriou J. Spuler S. Shavlakadze T. Lipid accumulation in dysferlin-deficient muscles.Am. J. Pathol. 2014; 184: 1668-1676Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, M. R. G.A. et and and J. Pathol. 2014; 184: Full Text Full Text PDF PubMed Scopus Google Scholar). is not in young mice months is pronounced by months in muscles, including and with by months J.R. Radley-Crabb H.G. T. P.G. M.D. and in muscular protein and J. 2013; PubMed Scopus Google Scholar). in A/J mice, to of the myofibers in and muscles are by adipocytes M. R. G.A. et and and J. Pathol. 2014; 184: Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. Radley-Crabb H.G. T. P.G. M.D. and in muscular protein and J. 2013; PubMed Scopus Google Scholar). MRI analysis muscle replacement by adipocytes and that the which is a slow muscle in the is of the muscles to this J. Fernandez-Torron R. LLauger J. James M.K. Mayhew A. Smith F.E. Moore U.R. Blamire A.M. Carlier P.G. Rufibach L. et al.Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials.J. Neurol. Neurosurg. Psychiatry. 2018; 89: 1071-1081Crossref PubMed Scopus (61) Google Scholar). a of is in dysferlin and mouse muscles (9.Grounds M.D. Terrill J.R. Radley-Crabb H.G. Robertson T. Papadimitriou J. Spuler S. Shavlakadze T. Lipid accumulation in dysferlin-deficient muscles.Am. J. Pathol. 2014; 184: 1668-1676Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, C. E. A. L. C. Dysferlinopathy and for Google Scholar), the striking are M. Angelini C. and in dysferlinopathy.Muscle Nerve. 2014; PubMed Scopus Google Scholar), associated with loss of and of (9.Grounds M.D. Terrill J.R. Radley-Crabb H.G. Robertson T. Papadimitriou J. Spuler S. Shavlakadze T. Lipid accumulation in dysferlin-deficient muscles.Am. J. Pathol. 2014; 184: 1668-1676Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, M. Angelini C. changes in dysferlinopathy membrane Pathol. PubMed Scopus Google Scholar), that for the later loss associated with replacement by adipocytes. To is of the to the marked intramyocellular lipid accumulation in the muscles of young mice and to the later progressive replacement of muscles by adipocytes in muscles M. Angelini C. Progress and challenges in diagnosis of dysferlinopathy.Muscle Nerve. 2016; 54: 821-835Crossref PubMed Scopus (47) Google Scholar). and changes that contribute to the intramyocellular lipid accumulation in BLAJ mice by whole-body energy homeostasis, adipose tissue skeletal muscle lipid metabolism, and the skeletal muscle in young adult male BLAJ and WT mice to changes in lipid metabolism BLAJ myofibers are the later onset of marked changes in histopathology and of BLAJ mice from the C57Bl/6J mice from a with to a energy from mice and by the and to the and of of in male mice from mice for and MRI was to lean and fat mass in mice. 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Angelini C. Progress and challenges in diagnosis of dysferlinopathy.Muscle Nerve. 2016; 54: 821-835Crossref PubMed Scopus (47) Google Scholar), we assessed the to in from mice, was BLAJ mass and muscle in WT and dysferlin-deficient BLAJ adipose adipose from mice that had for WT and 8 BLAJ mice for all WT and BLAJ mice, and 8 WT and BLAJ mice. are assessed by in a from mice that had for WT and 8 BLAJ mice for all WT and BLAJ mice, and 8 WT and BLAJ mice. are assessed by energy was assessed using the was by a in the in BLAJ mice a for in the BLAJ mice. energy was not to lean mass physical activity was increased in BLAJ mice and to in BLAJ mice, this not by WT BLAJ with this BLAJ mice than WT mice in the a in fat mass are associated with and in to an not the increased in BLAJ mice with and the of in this was not an which in whole-body of of and was not WT and BLAJ mice and and not or with this was in WT and BLAJ mice Dysferlinopathies are characterized by an accumulation of lipid and we that this result from skeletal muscle fatty acid to fatty acid and storage lipid in muscles from young adult mice. acid to increased in BLAJ with WT mice and this was associated with in fatty acid fatty acid storage increased in BLAJ with WT mice analysis was in the muscle of the mice not the due to a of tissue for the gene the protein that fatty acid was reduced in BLAJ with WT mice, the proteins that fatty acid not which the that the of by a fatty and was increased in BLAJ mice. 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The of lipid was to protein mass and the a in BLAJ to WT not in young adult mice and this was by analysis using a and by from observations of increased of in skeletal muscle from mice and (9.Grounds M.D. Terrill J.R. Radley-Crabb H.G. Robertson T. Papadimitriou J. Spuler S. Shavlakadze T. Lipid accumulation in dysferlin-deficient muscles.Am. J. Pathol. 2014; 184: 1668-1676Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, M. R. G.A. et and and J. 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The changes in by a marked in the for was a in which the for R. R. M. A. A. et in adipose tissue is by adipose 2004; PubMed Scopus Google Scholar), and an in in BLAJ with WT mice, which increased storage in myofibers the of to Full Text Full Text PDF PubMed Scopus Google Scholar). changes in gene are with the increased acid of fatty acid muscle of BLAJ mice, which the storage and the lipid myofibers to a pronounced of slow myofibers rather than myofibers (9.Grounds M.D. Terrill J.R. Radley-Crabb H.G. Robertson T. Papadimitriou J. Spuler S. Shavlakadze T. Lipid accumulation in dysferlin-deficient muscles.Am. J. Pathol. 2014; 184: 1668-1676Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), the of mice that is of slow type and myofibers is of this is the most skeletal muscle mouse and skeletal muscles with and Disord. PubMed Scopus Google Scholar). of muscles from BLAJ with WT mice a of dysferlin deficiency with muscles, the of in manifestation H. M.D. function of slow muscles, with in BLAJ PubMed Scopus Google Scholar). have implications for the dysferlinopathy MRI that the is of the first muscles changes J. Fernandez-Torron R. LLauger J. James M.K. Mayhew A. Smith F.E. Moore U.R. Blamire A.M. Carlier P.G. Rufibach L. et al.Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials.J. Neurol. Neurosurg. Psychiatry. 2018; 89: 1071-1081Crossref PubMed Scopus (61) Google Scholar). is that in BLAJ and WT mice in the muscles, BLAJ mice an increased for fatty acid to in in lipid metabolism the muscles the is slow type and the many C. H. R. et by which fatty acids of receptor activity in Full Text Full Text PDF PubMed Scopus Google Scholar, M. C. 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The activity of is by most by protein in with associated including and A. T. tissue and the of lipid 2016; PubMed Scopus Google Scholar). Dysferlin was identified a lipid protein in the of and the was for its lipid L. et of and dysferlin lipid from 2016; PubMed Scopus Google Scholar). dysferlin for of the that and this the of acids to skeletal muscle of this is to an of in BLAJ mice and in BLAJ and WT mice. that lipid accumulation associated with from increased fatty acid increased adipose tissue lipolysis and the reprogramming of skeletal muscle fatty acid metabolism toward lipid of is the marked accumulation of intramyocellular lipid and replacement of myofibers with adipocytes later in the the skeletal muscle lipidome of young adult BLAJ mice, we have the of lipid changes in muscles of the by adipocytes. The analysis lipid BLAJ and WT mice, with in a of including sphingolipids, phospholipids, cholesterol, and is that of and resealing are striking of muscles S. muscular dystrophy from loss of dysferlin is by J. Pathol. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar), and in mouse models indicate that of are to muscles N. Z. C. R. C. M.A. muscle and in the mouse of Lipid 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). the changes described in the most are that affect the of the sphingolipids, and lipid are all of the M. and fatty acids of and from skeletal Full Text PDF PubMed Google Scholar), and we marked changes in many of in BLAJ mice, that associated with of proteins of and in the are associated with loss of membrane in Z. M. L. A. The of to membrane and Full Text Full Text PDF PubMed Scopus Google this was not BLAJ and WT mice. lipid affect many membrane including that vesicle trafficking and transmembrane T. the role of in lipid metabolism to the of skeletal and muscle of Lipid Lipid 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. lipid and Lipid Full Text PDF PubMed Google Scholar). vesicle trafficking associated with resealing is a striking of muscles K. S. R. membrane in dysferlin-deficient muscular PubMed Scopus Google Scholar, L. Brown R.H. Dysferlin in membrane trafficking and repair.Traffic. PubMed Scopus Google Scholar, R. Dysferlin and muscle membrane PubMed Scopus Google Scholar). muscles to of to is by PubMed Scopus Google Scholar), with to M. R. G.A. et and and J. Pathol. 2014; 184: Full Text Full Text PDF PubMed Scopus Google Scholar), is that a in skeletal myofibers the resultant of M. M.A. of dysferlin in skeletal novel muscular J. Pathol. 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Smith F.E. Moore U.R. Blamire A.M. Carlier P.G. Rufibach L. et al.Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials.J. Neurol. Neurosurg. Psychiatry. 2018; 89: 1071-1081Crossref PubMed Scopus (61) Google Scholar). of male and the that was a in with type and postgrowth was a selective of type myofibers in that was pronounced with and had implications T. M. T. in skeletal from to 2014; PubMed Scopus Google Scholar). in and muscles of adult male are changes in many and early and H. in and of skeletal muscle from to PubMed Scopus Google Scholar). the of changes in dysferlinopathy onset and progression to in the of and novel using young adult BLAJ mice the role for in skeletal muscle and adipose tissue lipid metabolism an early manifestation that from with adverse for progressive with myofibers by adipocytes and loss of metabolism many clinical implications and The and for with the with adipose

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