1,721,054 research outputs found
Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects
Get PDFSarcoglycanopathies are a group of autosomal recessive muscle-wasting disorders caused by genetic defects in one of four cell membrane glycoproteins, alpha-, beta-, gamma- or delta-sarcoglycan. These four sarcoglycans form a subcomplex that is closely linked to the major dystrophin-associated protein complex, which is essential for membrane integrity during muscle contraction and provides a scaffold for important signalling molecules. Proper assembly, trafficking and targeting of the sarcoglycan complex is of vital importance, and mutations that severely perturb tetramer formation and localisation result in sarcoglycanopathy. Gene defects in one sarcoglycan cause the absence or reduced concentration of the other subunits. Most genetic defects generate mutated proteins that are degraded through the cell's quality control system; however, in many cases, conformational modifications do not affect the function of the protein, yet it is recognised as misfolded and prematurely degraded. Recent evidence shows that misfolded sarcoglycans could be rescued to the cell membrane by assisting their maturation along the ER secretory pathway. This review summarises the etiopathogenesis of sarcoglycanopathies and highlights the quality control machinery as a potential pharmacological target for therapy of these genetic disorders
Loss of Dystrophin and Some Dystrophin-Associated Proteins with Concomitant Signs of Apoptosis in Rat Leg Muscle Overworked in Extension
No full textActa Neuropathol. 2000 Dec;100(6):618-26.
Loss of dystrophin and some dystrophin-associated proteins with concomitant signs of apoptosis in rat leg muscle overworked in extension.
Biral D, Jakubiec-Puka A, Ciechomska I, Sandri M, Rossini K, Carraro U, Betto R.
Source
C.N.R. Unit for Muscle Biology and Physiopathology, Padova, Italy.
Abstract
This study investigated the basis for the high severity of damage to skeletal muscle due to eccentric exercise, i.e., to muscles generating force while lengthened. Fast and slow rat leg muscles maintained in an extended position were examined after 2-24 h of continuous stimulation. The treatment caused the injury to some regions of both muscles. Within the better preserved parts of the muscles, i.e., those without signs of necrotic processes, dystrophin, spectrin, and some of the dystrophin-associated proteins (beta-dystroglycan, alpha-sarcoglycan, and gamma-sarcoglycan) disappeared from sarcolemma of many fibers. The reduction or loss of dystrophin from the sarcolemma was more evident than that of other proteins examined, with sarcoglycans apparently being the most preserved. Several muscle fibers devoid of dystrophin contained apoptotic nuclei. Simultaneously, Bax, Bcl-2 and caspase-3 proteins appeared in many fibers. Our results indicate that a normal muscle overworking in an extended position undergoes the loss of several membrane skeletal proteins because of the excessive stress to the membrane cytoskeleton, which can lead to fiber death by either apoptosis or necrosis. This experimental model may represent a good model for mimicking the pathogenetic events in several muscular dystrophies.
PMID:
11078213
[PubMed - indexed for MEDLINE
Functional roles of dystrophin and of associated proteins. New insights for the sarcoglycans
No full textThe discovery of the dystrophin gene, whose mutations lead to Duchenne's and Becker's muscular dystrophy (DMD and BMD), represents the first important landmark by which, in the last ten years, molecular biology and genetic studies have revealed many of the molecular defects of the major muscular dystrophies. Very rapidly, several studies revealed the presence at skeletal and cardiac muscle sarcolemma of a group of proteins associated to dystrophin. This includes a set of five transmembrane glycoproteins, the sarcoglycans, whose physiological role, however, is still poorly understood. Dystrophin and the associated proteins are believed to play an important role in membrane stability and maintenance during muscle contraction and relaxation. However, the absence of sarcoglycans from sarcolemma does not appear to affect membrane integrity suggesting that these components of the dystrophin complex are recipients of other important functions. This review deals with recent advances in the knowledge of sarcoglycan function and organization that may give important insights into the pathogenetic mechanisms of muscular dystrophies
The role of sphingolipids in the control of skeletal muscle function: a review.
No full textIn this review, potential roles for the endogenous sphingolipid, sphingosine, and its derivatives are described for muscle cells. Sphingosine modulates the function of important calcium channels in muscle, including the ryanodine receptor (RyR) calcium release channel of the sarcoplasmic reticulum (SR). Sphingosine blocks calcium release through the SR ryanodine receptor and reduces the activity of single skeletal muscle RyR channels reconstituted into planar lipid bilayers. Sphingosine-blocked calcium release is coincident with the inhibitory effects of sphingosine on [3H]ryanodine binding to the RyR. The sphingomyelin signal transduction pathway has also been identified in both skeletal and cardiac muscle. A neutral form of sphingomyelinase (nSMase) enzyme has been localized to the junctional transverse tubule membrane. The high turnover of the SMase is responsible for the production of ceramide and sphingosine. HPLC analyses indicate that significant resting levels of sphingosine are present in muscle tissue. A model of excitation-contraction coupling is presented suggesting a potential role for this endogenous sphingolipid in normal muscle function. Putative roles for sphingolipid mediators in skeletal muscle dysfunction are also discussed. We hypothesize that sphingosine plays important roles in malignant hyperthermia and during the development of muscle fatigue
Polimorphism of myofibrillar proteins of rabbit skeletal muscle fibres. An electrophoretic study of single fibres
No full textRabbit predominantly fast-twitch-fibre and predominantly slow-twitch-fibre skeletal muscles of the hind limbs, the psoas, the diaphragm and the masseter muscles were fibre-typed by one-dimensional polyacrylamide-gel electrophoresis of the myofibrillar proteins of chemically skinned single fibres. Investigation of the distribution of fast-twitch-fibre and slow-twitch-fibre isoforms of myosin light chains and the type of myosin heavy chains, based on peptide 'maps' published in Cleveland. Fischer, Kirschner & Laemmli [(1977) J. Biol. Chem. 252, 1102-1106], allowed a classification of muscle fibres into four classes, corresponding to histochemical types I, IIA, IIB and IIC. Type I fibres with a pure slow-twitch-type of myosin were found to be characterized by a unique set of isoforms of troponins I, C and T, in agreement with the immunological data of Dhoot & Perry [(1979) Nature (London) 278, 714-718], by predominance of the beta-tropomyosin subunit and by the presence of a small amount of an additional tropomyosin subunit, apparently dissimilar from fast-twitch-fibre alpha-tropomyosin subunit. The myofibrillar composition of type IIB fast-twitch white fibres was the mirror image of that found for slow-twitch fibres in that the fast-twitch-fibre isoforms only of the troponin subunits were present and the alpha-tropomyosin subunit predominated. Type IIA fast-twitch red fibres showed a troponin subunit composition identical with that of type IIB fast-twitch white fibres. On the other hand, a unique type of myosin heavy chains was found to be associated with type IIA fibres. Furthermore, the myosin light-chain composition of these fibres was invariably characterized by a small amount of LC3F light chain and by a pattern that was either a pure fast-twitch-fibre light-chain pattern or a hybrid LC1F/LC2F/LC3F/LC1Sb light-chain pattern. By these criteria type IIA fibres could be distinguished from type IIC intermediate fibres, which showed coexistence of fast-twitch-fibre and slow-twitch-fibre forms of myosin light chains and of troponin subunits
Type 1, 2A, 2B myosin haevy chain electrophoretic analysis of rat muscle fibers
No full textMammalian skeletal muscles are mixture of three type of fibers: type 1, type 2A, and type 2B fibers. Immunological studies and proteolytic analysis of myosin heavy chains from the three type of fibers have demonstrated the presence of distinct myosin isoforms. By using typed single muscle fibers and improving an electrophoretic method we are able to resolve three distinct polypeptides which are demonstrate to correspond to type 1, 2A and 2B myosin heavy chain isoforms by using specific monoclonal antibodies. The analysis of single muscle fibers shows that different myosin heavy chain isoforms are frequently coexpressed in the same muscle fiber
Calcium sensitivity and myofibrillar protein isoforms of rat skinned skeletal muscle fibres
No full textWe investigated the calcium sensitivity for tension generation of different fibre types and the possible correlation between calcium sensitivity and the presence of distinct regulatory protein and myosin light chain (MLC) isoforms in rat skinned skeletal muscle fibres. Fibre types 1, 2A and 2B were identified by electrophoretic analysis of myosin heavy chain (MHC) isoforms. Fibres showing more than one MHC isoform were discarded. Type 1 fibres from the soleus showed a higher pCa (-log10 [Ca], where [ ] denotes concentration) threshold and a lower slope of pCa/tension curve than type 2 extensor digitorum longus (EDL) fibres; between type 2 fibres, type 2B showed the higher slope of pCa/tension curve. Type 1 fibres from different muscles showed similar calcium sensitivities when containing only the slow set of regulatory proteins and MLC; when both slow and fast isoforms were present, calcium sensitivity shifted toward fast type fibre values. Type 2A fibres from different muscles showed a similar calcium sensitivity, independently of the set (purely fast or mixed) of regulatory proteins and MLC. It is suggested that when both fast and slow isoforms of regulatory proteins and of MLC are present in a muscle fibre, calcium sensitivity is dictated mainly by the fast isoforms
Unveiling the degradative route of the V247M α-sarcoglycan mutant responsible for LGMD-2D.
No full textMany membrane and secretory proteins that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated into the cytosol and degraded by the proteasome. In applying rigid rules, however, quality control sometimes discharges proteins that, even though defective, retain their function. The unnecessary removal of such proteins represents the pathogenetic hallmark of diverse genetic diseases, in the case of ΔF508 mutant of cystic fibrosis transmembrane conductance regulator being probably the best known example. Recently, the inappropriate proteasomal degradation of skeletal muscle sarcoglycans (α, β, γ and δ) with missense mutation has been proposed to be at the bases of mild-to-severe forms of limb girdle muscular dystrophy (LGMD) known as type 2D, 2E, 2C and 2F, respectively. The quality control pathway responsible for sarcoglycan mutant disposal, however, is so far unexplored. Here we reveal key components of the degradative route of V247M α-sarcoglycan mutant, the second most frequently reported mutation in LGMD-2D. The disclosure of the pathway, which is led by the E3 ligases HRD1 and RFP2, permits to identify new potential druggable targets of a disease for which no effective therapy is at present available. Notably, we show that the pharmacological inhibition of HRD1 activity rescues the expression of V247-α-sarcoglycan both in a heterologous cell model and in myotubes derived from a LGMD-2D patient carrying the L31P/V247M mutations. This represents the first evidence that the activity of E3 ligases, the enzymes in charge of mutant fate, can be eligible for drug interventions to treat sarcoglycanopath
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