IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice

Denisse Valladares, Yildy Utreras-Mendoza, Cristian Campos, Camilo Morales, Alexis Diaz-Vegas, Ariel Contreras-Ferrat, Francisco Westermeier, Enrique Jaimovich, Saverio Marchi, Paolo Pinton, Sergio Lavandero

Resultado de la investigación: Article

1 Cita (Scopus)

Resumen

Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP3 receptor (IP3R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP3R restores muscle function. Moreover, we have shown that the IP3R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP3R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP3R was downregulated in mdx fibers. Pharmacological blockade of IP3R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP3R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP3R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP3R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP3R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function.

Idioma originalEnglish
Páginas (desde-hasta)3685-3695
Número de páginas11
PublicaciónBiochimica et Biophysica Acta - Molecular Basis of Disease
Volumen1864
N.º11
DOI
EstadoPublished - 1 nov 2018

Huella dactilar

Inositol 1,4,5-Trisphosphate Receptors
Skeletal Muscle Fibers
Autophagy
Mitochondrial Degradation
Duchenne Muscular Dystrophy
Mitochondrial Dynamics
Mitochondrial Membrane Potential
Pharmacology
Skeletal Muscle
Muscles
Mitochondria
Homeostasis
Down-Regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Citar esto

Valladares, D., Utreras-Mendoza, Y., Campos, C., Morales, C., Diaz-Vegas, A., Contreras-Ferrat, A., ... Lavandero, S. (2018). IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(11), 3685-3695. https://doi.org/10.1016/j.bbadis.2018.08.042
Valladares, Denisse ; Utreras-Mendoza, Yildy ; Campos, Cristian ; Morales, Camilo ; Diaz-Vegas, Alexis ; Contreras-Ferrat, Ariel ; Westermeier, Francisco ; Jaimovich, Enrique ; Marchi, Saverio ; Pinton, Paolo ; Lavandero, Sergio. / IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice. En: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2018 ; Vol. 1864, N.º 11. pp. 3685-3695.
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abstract = "Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP3 receptor (IP3R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP3R restores muscle function. Moreover, we have shown that the IP3R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP3R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP3R was downregulated in mdx fibers. Pharmacological blockade of IP3R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP3R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP3R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP3R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP3R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function.",
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Valladares, D, Utreras-Mendoza, Y, Campos, C, Morales, C, Diaz-Vegas, A, Contreras-Ferrat, A, Westermeier, F, Jaimovich, E, Marchi, S, Pinton, P & Lavandero, S 2018, 'IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1864, n.º 11, pp. 3685-3695. https://doi.org/10.1016/j.bbadis.2018.08.042

IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice. / Valladares, Denisse; Utreras-Mendoza, Yildy; Campos, Cristian; Morales, Camilo; Diaz-Vegas, Alexis; Contreras-Ferrat, Ariel; Westermeier, Francisco; Jaimovich, Enrique; Marchi, Saverio; Pinton, Paolo; Lavandero, Sergio.

En: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1864, N.º 11, 01.11.2018, p. 3685-3695.

Resultado de la investigación: Article

TY - JOUR

T1 - IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice

AU - Valladares, Denisse

AU - Utreras-Mendoza, Yildy

AU - Campos, Cristian

AU - Morales, Camilo

AU - Diaz-Vegas, Alexis

AU - Contreras-Ferrat, Ariel

AU - Westermeier, Francisco

AU - Jaimovich, Enrique

AU - Marchi, Saverio

AU - Pinton, Paolo

AU - Lavandero, Sergio

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP3 receptor (IP3R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP3R restores muscle function. Moreover, we have shown that the IP3R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP3R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP3R was downregulated in mdx fibers. Pharmacological blockade of IP3R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP3R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP3R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP3R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP3R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function.

AB - Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP3 receptor (IP3R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP3R restores muscle function. Moreover, we have shown that the IP3R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP3R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP3R was downregulated in mdx fibers. Pharmacological blockade of IP3R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP3R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP3R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP3R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP3R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function.

KW - Autophagy

KW - Inositol triphosphate receptor

KW - Mitochondria

KW - Mitophagy

KW - Muscle dystrophy

KW - Skeletal muscle

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U2 - 10.1016/j.bbadis.2018.08.042

DO - 10.1016/j.bbadis.2018.08.042

M3 - Article

AN - SCOPUS:85053076733

VL - 1864

SP - 3685

EP - 3695

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

IS - 11

ER -