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  • 1. Kurapati, Ramakrishna
    et al.
    McKenna, Caoimhe
    Lindqvist, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Williams, Debbie
    Simon, Michelle
    LeProust, Emily
    Baker, Jane
    Cheeseman, Michael
    Carroll, Natalie
    Denny, Paul
    Laval, Steve
    Lochmueller, Hanns
    Ochala, Julien
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Blanco, Gonzalo
    Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb2012Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, nr 8, s. 1706-1724Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.

  • 2.
    Lindqvist, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Cellular and Molecular Mechanisms Underlying Congenital Myopathy-related Weakness2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Congenital myopathies are a rare and heterogeneous group of diseases. They are primarily characterised by skeletal muscle weakness and disease-specific pathological features. They harshly limit ordinary life and in severe cases, these myopathies are associated with early death of the affected individuals. The congenital myopathies investigated in this thesis are nemaline myopathy and myofibrillar myopathy. These diseases are usually caused by missense mutations in genes encoding myofibrillar proteins, but the exact mechanisms by which the point mutations in these proteins cause the overall weakness remain mysterious. Hence, in this thesis two different nemaline myopathy-causing actin mutations and one myofibrillar myopathy-causing myosin-mutation found in both human patients and mouse models were used to investigate the cascades of molecular and cellular events leading to weakness.

    I performed a broad range of functional and structural experiments including skinned muscle fibre mechanics, small-angle X-ray scattering as well as immunoblotting and histochemical techniques. Interestingly, according to my results, point mutations in myosin and actin differently modify myosin binding to actin, cross-bridge formation and muscle fibre force production revealing divergent mechanisms, that is, gain versus loss of function (papers I, II and IV). In addition, one point mutation in actin appears to have muscle-specific effects.  The presence of that mutant protein in respiratory muscles, i.e. diaphragm, has indeed more damaging consequences on myofibrillar structure than in limb muscles complexifying the pathophysiological mechanisms (paper II).

    As numerous atrophic muscle fibres can be seen in congenital myopathies, I also considered this phenomenon as a contributing factor to weakness and characterised the underlying causes in presence of one actin mutation. My results highlighted a direct muscle-specific up-regulation of the ubiquitin-proteasome system (paper III).

    All together, my research work demonstrates that mutation- and muscle-specific mechanisms trigger the muscle weakness in congenital myopathies. This gives important insights into the pathophysiology of congenital myopathies and will undoubtedly help in designing future therapies.

    Delarbeten
    1. A myopathy-related actin mutation increases contractile function
    Öppna denna publikation i ny flik eller fönster >>A myopathy-related actin mutation increases contractile function
    Visa övriga...
    2012 (Engelska)Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, nr 5, s. 739-746Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.

    Nyckelord
    Nemaline myopathy, ACTA1 mutation, Skeletal muscle, Force, Actin, Myosin cross-bridge
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-173318 (URN)10.1007/s00401-012-0962-z (DOI)000302255000009 ()
    Tillgänglig från: 2012-04-25 Skapad: 2012-04-23 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy
    Öppna denna publikation i ny flik eller fönster >>Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy
    Visa övriga...
    2013 (Engelska)Ingår i: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 72, nr 6, s. 472-481Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Nemaline myopathy is the most common congenital myopathy and is caused by mutations in various genes such as ACTA1 (encoding skeletal alpha-actin). It is associated with limb and respiratory muscle weakness. Despite increasing clinical and scientific interest, the molecular and cellular events leading to such weakness remain unknown, which prevents the development of specific therapeutic interventions. To unravel the potential mechanisms involved, we dissected lower limb and diaphragm muscles from a knock-in mouse model of severe nemaline myopathy expressing the ACTA1 His40Tyr actin mutation found in human patients. We then studied a broad range of structural and functional characteristics assessing single-myofiber contraction, protein expression, and electron microscopy. One of the major findings in the diaphragm was the presence of numerous noncontractile areas (including disrupted sarcomeric structures and nemaline bodies). This greatly reduced the number of functional sarcomeres, decreased the force generation capacity at the muscle fiber level, and likely would contribute to respiratory weakness. In limb muscle, by contrast, there were fewer noncontractile areas and they did not seem to have a major role in the pathogenesis of weakness. These divergent muscle-specific results provide new important insights into the pathophysiology of severe nemaline myopathy and crucial information for future development of therapeutic strategies.

    Nyckelord
    Actin, Contractile dysfunction, Limb muscle, Nemaline myopathy, Respiratory muscle, Weakness
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-204291 (URN)10.1097/NEN.0b013e318293b1cc (DOI)000319454400003 ()
    Tillgänglig från: 2013-07-30 Skapad: 2013-07-29 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    3. Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathy
    Öppna denna publikation i ny flik eller fönster >>Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathy
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Nemaline myopathy, the most common congenital myopathy, is characterized by muscle fibre atrophy.  This compromises contractile performance and ultimately contributes to muscle weakness.  The pathogenic mechanisms remain obscure but may be related to an aberrant protein turnover rate due to an increased activation of the ubiquitin-proteasome pathway.  To verify, this hypothesis, in the present study, we used skeletal muscles from a transgenic mouse model of nemaline myopathy.  We then evaluated the expression of key proteins such as MuRF1 and atrogin-1.  In the slow-twitch soleus muscle, we observed a trend towards a higher level of atrogin-1 whereas in the fast-twitch tibialis anterior muscle, we revealed a greater expression of MuRF1.  These led to divergent effects on protein content and muscle fibre size.  Indeed, in the soleus, a general protein loss and atrophy was found whilst in tibialis anterior, a preferential myosin loss without any clear reduction in the mean muscle fibre size was noticed.  Overall these findings prove for the first time that in nemaline myopathy, the ubiquitin-proteasome pathway (i) is involved in the process of muscle wasting; (ii) is differentially activated in slow- and fast-twitch muscles; (iii) may be targeted as a future therapy to alleviate muscle wasting.

    Nyckelord
    myopathy, muscle wasting, atrophy, Murf1, atrogin-1
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-219403 (URN)
    Tillgänglig från: 2014-02-28 Skapad: 2014-02-28 Senast uppdaterad: 2014-04-29
    4. The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4(L342Q)
    Öppna denna publikation i ny flik eller fönster >>The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4(L342Q)
    2013 (Engelska)Ingår i: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, nr 3, s. 834-840Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Myosinopathies have emerged as a new group of diseases and are caused by mutations in genes encoding myosin heavy chain (MyHC) isoforms. One major hallmark of these diseases is skeletal muscle weakness or paralysis, but the underlying molecular mechanisms remain unclear. Here, we have undertaken a detailed functional study of muscle fibers from Myh4(arl) mice, which carry a mutation that provokes an L342Q change within the catalytic domain of the type IIb skeletal muscle myosin protein MYH4. Because homozygous animals develop rapid muscle-structure disruption and lower-limb paralysis, they must be killed by postnatal day 13, so all experiments were performed using skeletal muscles from adult heterozygous animals (Myh4(arl)/+). Myh4(arl)/+ mice contain MYH4(L342Q) expressed at 7% of the levels of the wild-type (WT) protein, and are overtly and histologically normal. However, mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized fibers revealed, upon maximal Ca2+ activation, higher stiffness as well as altered meridional and equatorial reflections in Myh4(arl)/+ mice when compared with age-matched WT animals. Under rigor conditions, by contrast, no difference was observed between Myh4(arl)/+ and WT mice. Altogether, these findings prove that, in adult MYH4(L342Q) heterozygous mice, the transition from weak to strong myosin cross-bridge binding is facilitated, increasing the number of strongly attached myosin heads, thus enhancing force production. These changes are predictably exacerbated in the type IIb fibers of homozygous mice, in which the embryonic myosin isoform is fully replaced by MYH4(L342Q), leading to a hypercontraction, muscle-structure disruption and lower-limb paralysis. Overall, these findings provide important insights into the molecular pathogenesis of skeletal myosinopathies.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-202382 (URN)10.1242/dmm.011155 (DOI)000318847400029 ()
    Tillgänglig från: 2013-06-24 Skapad: 2013-06-24 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
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  • 3.
    Lindqvist, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Cheng, Arthur J.
    Renaud, Guillaume
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Hardeman, Edna C.
    Ochala, Julien
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy2013Ingår i: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 72, nr 6, s. 472-481Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nemaline myopathy is the most common congenital myopathy and is caused by mutations in various genes such as ACTA1 (encoding skeletal alpha-actin). It is associated with limb and respiratory muscle weakness. Despite increasing clinical and scientific interest, the molecular and cellular events leading to such weakness remain unknown, which prevents the development of specific therapeutic interventions. To unravel the potential mechanisms involved, we dissected lower limb and diaphragm muscles from a knock-in mouse model of severe nemaline myopathy expressing the ACTA1 His40Tyr actin mutation found in human patients. We then studied a broad range of structural and functional characteristics assessing single-myofiber contraction, protein expression, and electron microscopy. One of the major findings in the diaphragm was the presence of numerous noncontractile areas (including disrupted sarcomeric structures and nemaline bodies). This greatly reduced the number of functional sarcomeres, decreased the force generation capacity at the muscle fiber level, and likely would contribute to respiratory weakness. In limb muscle, by contrast, there were fewer noncontractile areas and they did not seem to have a major role in the pathogenesis of weakness. These divergent muscle-specific results provide new important insights into the pathophysiology of severe nemaline myopathy and crucial information for future development of therapeutic strategies.

  • 4.
    Lindqvist, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Hardeman, E
    Ochala, J
    Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathyManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Nemaline myopathy, the most common congenital myopathy, is characterized by muscle fibre atrophy.  This compromises contractile performance and ultimately contributes to muscle weakness.  The pathogenic mechanisms remain obscure but may be related to an aberrant protein turnover rate due to an increased activation of the ubiquitin-proteasome pathway.  To verify, this hypothesis, in the present study, we used skeletal muscles from a transgenic mouse model of nemaline myopathy.  We then evaluated the expression of key proteins such as MuRF1 and atrogin-1.  In the slow-twitch soleus muscle, we observed a trend towards a higher level of atrogin-1 whereas in the fast-twitch tibialis anterior muscle, we revealed a greater expression of MuRF1.  These led to divergent effects on protein content and muscle fibre size.  Indeed, in the soleus, a general protein loss and atrophy was found whilst in tibialis anterior, a preferential myosin loss without any clear reduction in the mean muscle fibre size was noticed.  Overall these findings prove for the first time that in nemaline myopathy, the ubiquitin-proteasome pathway (i) is involved in the process of muscle wasting; (ii) is differentially activated in slow- and fast-twitch muscles; (iii) may be targeted as a future therapy to alleviate muscle wasting.

  • 5.
    Lindqvist, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Iwamoto, Hiroyuki
    Blanco, Gonzalo
    Ochala, Julien
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4(L342Q)2013Ingår i: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, nr 3, s. 834-840Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Myosinopathies have emerged as a new group of diseases and are caused by mutations in genes encoding myosin heavy chain (MyHC) isoforms. One major hallmark of these diseases is skeletal muscle weakness or paralysis, but the underlying molecular mechanisms remain unclear. Here, we have undertaken a detailed functional study of muscle fibers from Myh4(arl) mice, which carry a mutation that provokes an L342Q change within the catalytic domain of the type IIb skeletal muscle myosin protein MYH4. Because homozygous animals develop rapid muscle-structure disruption and lower-limb paralysis, they must be killed by postnatal day 13, so all experiments were performed using skeletal muscles from adult heterozygous animals (Myh4(arl)/+). Myh4(arl)/+ mice contain MYH4(L342Q) expressed at 7% of the levels of the wild-type (WT) protein, and are overtly and histologically normal. However, mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized fibers revealed, upon maximal Ca2+ activation, higher stiffness as well as altered meridional and equatorial reflections in Myh4(arl)/+ mice when compared with age-matched WT animals. Under rigor conditions, by contrast, no difference was observed between Myh4(arl)/+ and WT mice. Altogether, these findings prove that, in adult MYH4(L342Q) heterozygous mice, the transition from weak to strong myosin cross-bridge binding is facilitated, increasing the number of strongly attached myosin heads, thus enhancing force production. These changes are predictably exacerbated in the type IIb fibers of homozygous mice, in which the embryonic myosin isoform is fully replaced by MYH4(L342Q), leading to a hypercontraction, muscle-structure disruption and lower-limb paralysis. Overall, these findings provide important insights into the molecular pathogenesis of skeletal myosinopathies.

    Ladda ner fulltext (pdf)
    fulltext
  • 6.
    Lindqvist, Johan M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Ochala, Julien
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    The Cardiac Alkali Myosin Light Chain Can Restore Skeletal Muscle Function in a Mouse Model of Nemaline Myopathy2013Ingår i: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, s. S68-S68Artikel i tidskrift (Övrigt vetenskapligt)
  • 7.
    Lindqvist, Johan M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Ochala, Julien
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    The H40Y alpha-actin mutation differently affects limb and respiratory muscle contraction2012Ingår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, nr 9-10, s. 844-844Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Nemaline myopathy is the most common of the congenital non-dystrophic myopathies, with an estimated incidence of 1:50,000. The severe form of this disease is characterized by generalized weakness especially affecting limb and respiratory muscles. Questions that remain unanswered are (i) whether limb and respiratory muscles are affected to the same extent, and (ii) whether the underlying mechanisms are similar. The aim of the present study was to address these questions in a novel transgenic mouse model of severe nemaline myopathy. This model expresses the heterozygous amino acid substitution, H40Y, in skeletal α-actin. Hence, we dissected EDL and diaphragm muscles and evaluated the contraction mechanism. To our surprise, we observed muscle-specific defects that will be presented during the conference. These findings give valuable information for future potential therapeutic interventions.

  • 8.
    Lindqvist, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Penisson-Besnier, Isabelle
    Iwamoto, Hiroyuki
    Li, Meishan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Yagi, Naoto
    Ochala, Julien
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    A myopathy-related actin mutation increases contractile function2012Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, nr 5, s. 739-746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.

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