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

Abstract

ized by the onset of muscle weakness and loss of function usually in the late teens and with slow progression (2). Dysferlinopathies include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, with the proximal and distal limb-girdle muscles being the main muscles affected (2-4). Mouse models of dysferlinopathy harboring dysferlin deficiency or deletion (5-8) consistently have a late onset of dystropathology, by about 8 months of age, with pronounced replacement of myofibers by adipocytes (9). Dysferlin is a member of a large ferlin family of transmembrane proteins that are involved in protein vesicle trafficking and fusion (10), with dysferlin initially attracting attention due to its role in the resealing of experimentally damaged sarcolemma (11-13). Dysferlin is localized in intracellular membranes of skeletal muscles such as Ttubules and sarcoplasmic reticulum (14), plays a role in Ttubule formation (15), and appears to be involved in calcium homeostasis related to excitation-contraction coupling (16-18). Dysferlin is highly expressed in skeletal myofibers but is also present in many other tissues (19) and cells, including adipocytes (20), macrophages (21), and endothelium (22). Two striking features of human and mouse dysferlin-deficient muscles are the accumulation of many lipid droplets within myofibers and, at a later age, the apparent replacement of myofibers with extramyocellular adipocytes (9, 15). Histopathology is not evident in young mice aged 3 months but is pronounced by 8-12 months in some muscles, including psoas and quadriceps, with increasing severity by 19 months (23). Indeed, in older Dysf-deficient A/J mice, 20% to 40% of the myofibers in quadriceps and psoas muscles are replaced by adipocytes (15, 23). In humans, Abstract 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 repro...

Blockade of Hemichannels Normalizes the Differentiation Fate of Myoblasts and Features of Skeletal Muscles from Dysferlin-Deficient Mice

“…A characteristic histological feature of dysferlinopathies is the accumulation of fat in skeletal muscles [ 13 , 14 ] and eventually the replacement of muscle fibers by adipose cells [ 4 ]. Since we have previously found high activity of Cx HCs in a dysferlin deficient human cell line [ 5 ] and dysferlin deficient patients and skeletal muscles of blAJ mice present fat accumulation [ 13 , 14 , 15 ], we speculated that some muscle precursor cells might acquire adipogenic commitment due to the elevated Cx HC activity.…”

“…Thus, the involvement of an additional and critical pathological mechanism in muscular degeneration remains unknown. A peculiar change of dysferlin deficient skeletal muscles that remains without explanation is the accumulation of fat tissue [ 3 , 4 ]. In this regard, we have suggested that de novo expression of connexin hemichannels (Cx HCs) might participate in muscle changes of dysferlinopathies as a plausible hypothesis [ 5 ].…”

Compound heterozygous DYSF variants causing limb‐girdle muscular dystrophy type 2B in a Chinese family

“…Being a member of the ferlin family, dysferlin plays a key role in the active process of repairing muscle membrane lesions and can be widely expressed in a variety of tissues and cells, including skeletal and cardiac muscles, lung, kidney, brain, adipocytes and monocytes 23,24 . Being involved in T‐tubule formation and myogenesis, dysferlin contains a short carboxy‐terminal transmembrane domain and seven amino‐terminal C2 domains (C2A‐C2G) with a DYSF domain localized between C2C and C2D, among which the C2A domain binds to phospholipids in the form of Ca 2+ dependence 25–29 . Patients with LGMD2B may have deficient or absent dysferlin as a result of variants in the DYSF gene.…”

Iron accumulation in skeletal muscles of old mice is associated with impaired regeneration after ischaemia–reperfusion damage

“…The respiratory exchange ratio was calculated as VCO 2 /VO 2 . Energy expenditure was calculated from VO 2 and respiratory exchange ratio using Weir constants and normalized to lean mass 24 . Food and water intake were recorded every 15 min.…”