Abstract
Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death1. Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D (Ppif) rendered mitochondria largely insensitive to the calcium overload–induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking δ-sarcoglycan (Scgd−/− mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2, encoding the α-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd−/− mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Durbeej, M. & Campbell, K.P. Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. Curr. Opin. Genet. Dev. 12, 349–361 (2002).
Lapidos, K.A., Kakkar, R. & McNally, E.M. The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ. Res. 94, 1023–1031 (2004).
Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003).
Whitehead, N.P., Yeung, E.W. & Allen, D.G. Muscle damage in mdx (dystrophic) mice: role of calcium and reactive oxygen species. Clin. Exp. Pharmacol. Physiol. 33, 657–662 (2006).
Turner, P.R., Westwood, T., Regen, C.M. & Steinhardt, R.A. Increased protein degradation results from elevated free calcium levels found in muscle from mdx mice. Nature 335, 735–738 (1988).
Mallouk, N., Jacquemond, V. & Allard, B. Elevated subsarcolemmal Ca2+ in mdx mouse skeletal muscle fibers detected with Ca2+-activated K. channels. Proc. Natl. Acad. Sci. USA 97, 4950–4955 (2000).
Zamzami, N. & Kroemer, G. The mitochondrion in apoptosis: how Pandora's box opens. Nat. Rev. Mol. Cell Biol. 2, 67–71 (2001).
Baines, C.P. et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662 (2005).
Nakagawa, T. et al. Cyclophilin D–dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652–658 (2005).
Basso, E. et al. Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J. Biol. Chem. 280, 18558–18561 (2005).
Schinzel, A.C. et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl. Acad. Sci. USA 102, 12005–12010 (2005).
Li, B. et al. Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart. Circ. Res. 84, 1007–1019 (1999).
Kuang, W. et al. Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models. J. Clin. Invest. 102, 844–852 (1998).
Stupka, N., Gregorevic, P., Plant, D.R. & Lynch, G.S. The calcineurin signal transduction pathway is essential for successful muscle regeneration in mdx dystrophic mice. Acta Neuropathol. 107, 299–310 (2004).
Friday, B.B., Horsley, V. & Pavlath, G.K. Calcineurin activity is required for the initiation of skeletal muscle differentiation. J. Cell Biol. 149, 657–666 (2000).
Chakkalakal, J.V. et al. Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice. Hum. Mol. Genet. 13, 379–388 (2004).
Stupka, N. et al. Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice. J. Physiol. (Lond.) 575, 645–656 (2006).
Hansson, M.J. et al. The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J. Bioenerg. Biomembr. 36, 407–413 (2004).
Flisiak, R. et al. The cyclophilin inhibitor Debio-025 had a potent dual anti-HIV and anti-HCV activity in treatment-naive HIV/HCV co-infected subjects. Hepatology 44 (Suppl 1.), 609A (2006).
Khaspekov, L., Friberg, H., Halestrap, A., Viktorov, I. & Wieloch, T. Cyclosporin A and its nonimmunosuppressive analogue N-Me-Val-4–cyclosporin A mitigate glucose/oxygen deprivation–induced damage to rat cultured hippocampal neurons. Eur. J. Neurosci. 11, 3194–3198 (1999).
Nakayama, H. et al. Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J. Clin. Invest. 117, 2431–2444 (2007).
Irwin, W.A. et al. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat. Genet. 35, 367–371 (2003).
Angelin, A. et al. Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins. Proc. Natl. Acad. Sci. USA 104, 991–996 (2007).
Forte, M. et al. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc. Natl. Acad. Sci. USA 104, 7558–7563 (2007).
Hack, A.A. et al. Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex. J. Cell Sci. 113, 2535–2544 (2000).
Fontaine, E. et al. Regulation of the permeability transition pore in skeletal muscle mitochondria. Modulation by electron flow through the respiratory chain complex I. J. Biol. Chem. 273, 12662–12668 (1998).
Parsons, S.A., Millay, D.P., Sargent, M.A., McNally, E.M. & Molkentin, J.D. Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy. Am. J. Pathol. 168, 1975–1985 (2006).
Suzuki, K. et al. Overexpression of interleukin-1 receptor antagonist provides cardioprotection against ischemia-reperfusion injury associated with reduction in apoptosis. Circulation 104, I308–I313 (2001).
Fewell, J.G. et al. A treadmill exercise regimen for identifying cardiovascular phenotypes in transgenic mice. Am. J. Physiol. 273, H1595–H1605 (1997).
Barton-Davis, E.R. et al. Viral-mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc. Natl. Acad. Sci. USA 95, 15603–15607 (1998).
Acknowledgements
This work was supported by grants from the National Institutes of Health (J.D.M., J.R.), an award from the Jain Foundation (J.D.M.), the Fondation Leducq (J.D.M.) and The Paul Wellstone Muscular Dystrophy Cooperative Research Center of the National Institutes of Health (U54 AR052646 to H.L.S. and E.R.B.). D.P.M. was supported by National Institutes of Health training grant 5 T32 HL07382 (principal investigator A. Schwartz). We would like to thank X. Xiao at the University of Pittsburgh for supplying the Lama2−/− mice under permission from E. Engvall at the Burnham Institute. We would also like to thank E. McNally (University of Chicago) for the Scgd−/− mice.
Author information
Authors and Affiliations
Contributions
D.P.M. performed most of the experiments with technical help from M.A.S., C.P.B. and H.O. E.R.B. performed the force measurements in EDL within the Wellstone center grant to H.L.S. G.V. consulted on studies with Debio-025 and provided the compound. J.R. provided support through the use of electron microscopy. J.D.M. planned and supervised all experimentation.
Corresponding author
Ethics declarations
Competing interests
One author, G.V., is an employee of DebioPharm, which supplied us with the Debio-025 compound.
Supplementary information
Supplementary Text and Figures
Supplementary Figs. 1–7 (PDF 1118 kb)
Rights and permissions
About this article
Cite this article
Millay, D., Sargent, M., Osinska, H. et al. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med 14, 442–447 (2008). https://doi.org/10.1038/nm1736
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1736
This article is cited by
-
Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions
Cell Death & Differentiation (2023)
-
The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction
Communications Biology (2022)
-
Computational Model of the Effect of Mitochondrial Dysfunction on Excitation–Contraction Coupling in Skeletal Muscle
Bulletin of Mathematical Biology (2022)
-
The mitochondrial permeability transition phenomenon elucidated by cryo-EM reveals the genuine impact of calcium overload on mitochondrial structure and function
Scientific Reports (2021)
-
APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β
Nature Aging (2021)