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Is the fundamental pathology in Duchenne's muscular dystrophy caused by a failure of glycogenolysis–glycolysis in costameres?

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Abstract

Duchenne muscular dystrophy (DMD) is the most common form of progressive childhood muscular dystrophy associated with weakness of limbs, loss of ambulation, heart weakness and early death. The mutations causing either loss-of-expression or function of the full-length protein dystrophin (Dp427) from the DMD gene are responsible for the disease pathology. Dp427 forms a part of the large dystroglycan complex, called DAPC, in the sarcolemma, and its absence derails muscle contraction. Muscle biopsies from DMD patients show an overactivation of excitation-contraction-coupling (ECC) activable calcium incursion, sarcolemmal ROS production, NHE1 activation, IL6 secretion, etc. The signalling pathways, like Akt/PBK, STAT3, p38MAPK, and ERK1/2, are also hyperactive in DMD. These pathways are responsible for post-mitotic trophic growth and metabolic adaptation, in response to exercise in healthy muscles, but cause atrophy and cell death in dystrophic muscles. We hypothesize that the metabolic background of repressed glycolysis in DMD, as opposed to excess glycolysis seen in cancers or healthy contracting muscles, changes the outcome of these ‘growth pathways’. The reduced glycolysis has been considered a secondary outcome of the cytoskeletal disruptions seen in DMD. Given the cytoskeleton-crosslinking ability of the glycolytic enzymes, we hypothesize that the failure of glycogenolytic and glycolytic enzymes to congregate is the primary pathology, which then affects the subsarcolemmal cytoskeletal organization in costameres and initiates the pathophysiology associated with DMD, giving rise to the tissue-specific differences in disease progression between muscle, heart and brain. The lacunae in the regulation of the key components of the hypothesized metabolome, and the limitations of this theory are deliberated. The considerations for developing future therapies based on known pathological processes are also discussed.

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Acknowledgements

We thank all researchers working on DMD and apologize to those whose work could not be cited due to space limitations or ignorance. A special thanks to Dr Isha Desai, Dr Saroj Jawkar and Amartya Mukherjee for endless discussion around the hypothesis and manuscript editing. Dr Somit Dutta, for his help with the figures. We also would like to thank the reviewer/s for their critical comments and suggestions. This review is part of a project funded by DST (SR/WOS-A/LS-273/2017) to VN and DST-SERB grant to UN (EMR/2016/004563).

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Authors and Affiliations

  1. Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, India

    Vishakha Nesari & Suresh Balakrishnan

  2. Indian Institute of Science, Bengaluru, 560 012, India

    Upendra Nongthomba

Authors
  1. Vishakha Nesari
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  2. Suresh Balakrishnan
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  3. Upendra Nongthomba
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Contributions

VN, SB and UN conceived the idea, and VN wrote the initial draft with inputs from UN. All authors have read and agreed to the manuscript submitted.

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Correspondence to Upendra Nongthomba.

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Corresponding editor: Durgadas P. Kasbekar

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Nesari, V., Balakrishnan, S. & Nongthomba, U. Is the fundamental pathology in Duchenne's muscular dystrophy caused by a failure of glycogenolysis–glycolysis in costameres?. J Genet 102, 13 (2023). https://doi.org/10.1007/s12041-022-01410-w

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  • DOI: https://doi.org/10.1007/s12041-022-01410-w

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