The I4895T mutation in the type 1 ryanodine receptor induces fiber-type specific alterations in skeletal muscle that mimic premature aging
Simona Boncompagni
IIM - Interuniversitary Institute of Myology, DNI – Department of Neuroscience and Imaging, Ce.S.I.- Centro Scienze dell’Invecchiamento, University of Studi G. d’Annunzio , 66013 Chieti, Italy
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
Search for more papers by this authorRyan E. Loy
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Search for more papers by this authorRobert T. Dirksen
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Search for more papers by this authorClara Franzini-Armstrong
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
Search for more papers by this authorSimona Boncompagni
IIM - Interuniversitary Institute of Myology, DNI – Department of Neuroscience and Imaging, Ce.S.I.- Centro Scienze dell’Invecchiamento, University of Studi G. d’Annunzio , 66013 Chieti, Italy
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
Search for more papers by this authorRyan E. Loy
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Search for more papers by this authorRobert T. Dirksen
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Search for more papers by this authorClara Franzini-Armstrong
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
Search for more papers by this authorSummary
The I4898T (IT) mutation in type 1 ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum (SR) is linked to a form of central core disease (CCD) in humans and results in a nonleaky channel and excitation–contraction uncoupling. We characterized age-dependent and fiber-type-dependent alterations in muscle ultrastructure, as well as the magnitude and spatiotemporal properties of evoked Ca2+ release in heterozygous Ryr1I4895T/WT (IT/+) knock-in mice on a mixed genetic background. The results indicate a classical but mild CCD phenotype that includes muscle weakness and the presence of mitochondrial-deficient areas in type I fibers. Electrically evoked Ca2+ release is significantly reduced in single flexor digitorum brevis (FDB) fibers from young and old IT/+ mice. Structural changes are strongly fiber-type specific, affecting type I and IIB/IIX fibers in very distinct ways, and sparing type IIA fibers. Ultrastructural alterations in our IT/+ mice are also present in wild type, but at a lower frequency and older ages, suggesting that the disease mutation on the mixed background promotes an acceleration of normal age-dependent changes. The observed functional and structural alterations and their similarity to age-associated changes are entirely consistent with the known properties of the mutated channel, which result in reduced calcium release as is also observed in normal aging muscle. In strong contrast to these observations, a subset of patients with the analogous human heterozygous mutation and IT/+ mice on an inbred 129S2/SvPasCrl background exhibit a more severe disease phenotype, which is not directly consistent with the mutated channel properties.
Supporting Information
Fig. S1 Longitudinal triads are frequently observed in 12 months EDL fibers from IT/+ mice.
Fig. S2 Nemaline Rods are present in aged soleus muscles from WT mice.
Fig. S3 Dissection damage is well detectable in whole mounts for the light microscope.
Fig. S4 Contractures in fibers from WT and IT/+ fibers have similar characteristics.
Fig. S5 Simulation and detection threshold assessment of non-homogeneous Ca2+ release.
Table S1 Frequency of contractures in fibers from fixed WT and IT/+ muscles.
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