Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Overview

Journal Front Physiol

Date 2021 Apr 26

PMID 33897454

Citations 57

Authors

Satvik Mareedu

Emily D Million

Dongsheng Duan

Gopal J Babu

Affiliations

Soon will be listed here.

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium ( ) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca homeostasis as potential therapies for DMD.

Citing Articles

Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mice.

Stephenson K, Barron A, Rae M, OMalley D Brain Behav Immun Health. 2025; 43:100935.

PMID: 39867844 PMC: 11762146. DOI: 10.1016/j.bbih.2024.100935.

Therapeutic Efficacy of Medicinal Plants with Allopathic Medicine in Musculoskeletal Diseases.

Rajalekshmi R, Agrawal D Int J Plant Anim Environ Sci. 2025; 14(4):104-129.

PMID: 39866300 PMC: 11765655. DOI: 10.26502/ijpaes.4490170.

Skeletal muscle disorders as risk factors for type 2 diabetes.

Tammineni E, Manno C, Oza G, Figueroa L Mol Cell Endocrinol. 2025; 599:112466.

PMID: 39848431 PMC: 11886953. DOI: 10.1016/j.mce.2025.112466.

Reduced voltage-activated Ca2+ release flux in muscle fibers from a rat model of Duchenne dystrophy.

Schreiber J, Rotard L, Tourneur Y, Lafoux A, Berthier C, Allard B J Gen Physiol. 2024; 157(2).

PMID: 39718509 PMC: 11668172. DOI: 10.1085/jgp.202413588.

Duchenne Muscular Dystrophy in Two Half-Brothers Due to Inherited 306 Kb Inverted Insertion of 10p15.1 into Intron 44 of the Dp427m Transcript of the Gene.

Jepsen W, Fazenbaker A, Ramsey K, Bonfitto A, Naymik M, Turner B Int J Mol Sci. 2024; 25(22).

PMID: 39595988 PMC: 11593467. DOI: 10.3390/ijms252211922.

References

Yasuda S, Townsend D, Michele D, Favre E, Day S, Metzger J . Dystrophic heart failure blocked by membrane sealant poloxamer. Nature. 2005; 436(7053):1025-9. DOI: 10.1038/nature03844. View

Nakada T, Kashihara T, Komatsu M, Kojima K, Takeshita T, Yamada M . Physical interaction of junctophilin and the Ca1.1 C terminus is crucial for skeletal muscle contraction. Proc Natl Acad Sci U S A. 2018; 115(17):4507-4512. PMC: 5924888. DOI: 10.1073/pnas.1716649115. View

Lanner J, Georgiou D, Joshi A, Hamilton S . Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol. 2010; 2(11):a003996. PMC: 2964179. DOI: 10.1101/cshperspect.a003996. View

Mendell J, Lloyd-Puryear M . Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy. Muscle Nerve. 2013; 48(1):21-6. DOI: 10.1002/mus.23810. View

Martins de Brito O, Scorrano L . Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008; 456(7222):605-10. DOI: 10.1038/nature07534. View

Head S . Branched fibres in old dystrophic mdx muscle are associated with mechanical weakening of the sarcolemma, abnormal Ca2+ transients and a breakdown of Ca2+ homeostasis during fatigue. Exp Physiol. 2010; 95(5):641-56. DOI: 10.1113/expphysiol.2009.052019. View

Bella P, Farini A, Banfi S, Parolini D, Tonna N, Meregalli M . Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy. EMBO Mol Med. 2019; 12(1):e11019. PMC: 6949491. DOI: 10.15252/emmm.201911019. View

Kwon H, Kwon B, Kim G, Chae J, Park J, Bae E . The effect of enalapril and carvedilol on left ventricular dysfunction in middle childhood and adolescent patients with muscular dystrophy. Korean Circ J. 2012; 42(3):184-91. PMC: 3318090. DOI: 10.4070/kcj.2012.42.3.184. View

Schiavone M, Zulian A, Menazza S, Petronilli V, Argenton F, Merlini L . Alisporivir rescues defective mitochondrial respiration in Duchenne muscular dystrophy. Pharmacol Res. 2017; 125(Pt B):122-131. DOI: 10.1016/j.phrs.2017.09.001. View

10.

Niranjan N, Mareedu S, Tian Y, Kodippili K, Fefelova N, Voit A . Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy. Am J Physiol Cell Physiol. 2019; 317(4):C813-C824. PMC: 6850989. DOI: 10.1152/ajpcell.00146.2019. View

11.

Ferretti R, Marques M, Pertille A, Neto H . Sarcoplasmic-endoplasmic-reticulum Ca2+-ATPase and calsequestrin are overexpressed in spared intrinsic laryngeal muscles of dystrophin-deficient mdx mice. Muscle Nerve. 2009; 39(5):609-15. DOI: 10.1002/mus.21154. View

12.

Smith W, Dirks A, Sugiura T, Muller S, Scarpace P, Powers S . Alteration of contractile force and mass in the senescent diaphragm with beta(2)-agonist treatment. J Appl Physiol (1985). 2002; 92(3):941-8. DOI: 10.1152/japplphysiol.00576.2001. View

13.

Robin G, Berthier C, Allard B . Sarcoplasmic reticulum Ca2+ permeation explored from the lumen side in mdx muscle fibers under voltage control. J Gen Physiol. 2012; 139(3):209-18. PMC: 3289961. DOI: 10.1085/jgp.201110738. View

14.

Gehrig S, van der Poel C, Sayer T, Schertzer J, Henstridge D, Church J . Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. Nature. 2012; 484(7394):394-8. DOI: 10.1038/nature10980. View

15.

Iwata Y, Katanosaka Y, Arai Y, Shigekawa M, Wakabayashi S . Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models. Hum Mol Genet. 2008; 18(5):824-34. DOI: 10.1093/hmg/ddn408. View

16.

Alderton J, Steinhardt R . Calcium influx through calcium leak channels is responsible for the elevated levels of calcium-dependent proteolysis in dystrophic myotubes. J Biol Chem. 2000; 275(13):9452-60. DOI: 10.1074/jbc.275.13.9452. View

17.

Chan S, Head S . The role of branched fibres in the pathogenesis of Duchenne muscular dystrophy. Exp Physiol. 2011; 96(6):564-71. DOI: 10.1113/expphysiol.2010.056713. View

18.

Deval E, Levitsky D, Marchand E, Cantereau A, Raymond G, Cognard C . Na(+)/Ca(2+) exchange in human myotubes: intracellular calcium rises in response to external sodium depletion are enhanced in DMD. Neuromuscul Disord. 2002; 12(7-8):665-73. DOI: 10.1016/s0960-8966(02)00022-6. View

19.

Lyon A, Babalis D, Morley-Smith A, Hedger M, Suarez Barrientos A, Foldes G . Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL. Gene Ther. 2020; 27(12):579-590. PMC: 7744277. DOI: 10.1038/s41434-020-0171-7. View

20.

Lohan J, Ohlendieck K . Drastic reduction in the luminal Ca2+ -binding proteins calsequestrin and sarcalumenin in dystrophin-deficient cardiac muscle. Biochim Biophys Acta. 2004; 1689(3):252-8. DOI: 10.1016/j.bbadis.2004.04.002. View