Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle

Caterina Marchioretti, Giulia Zanetti, Marco Pirazzini, Gaia Gherardi, Leonardo Nogara, Roberta Andreotti, Paolo Martini, Lorenzo Marcucci, Marta Canato, Samir R. Nath, Emanuela Zuccaro, Mathilde Chivet, Cristina Mammucari, Marco Pacifici, Anna Raffaello, Rosario Rizzuto, Andrea Mattarei, Maria A. Desbats, Leonardo Salviati, Aram Megighian, Gianni Sorarù, Elena Pegoraro, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Chiara Romualdi, Andrew P. Lieberman, Gopal J. Babu, Marco Sandri, Bert Blaauw, Manuela Basso and Maria Pennuto ()
Additional contact information
Caterina Marchioretti: University of Padova
Giulia Zanetti: University of Padova
Marco Pirazzini: University of Padova
Gaia Gherardi: University of Padova
Leonardo Nogara: University of Padova
Roberta Andreotti: University of Padova
Paolo Martini: University of Brescia
Lorenzo Marcucci: University of Padova
Marta Canato: University of Padova
Samir R. Nath: University of Michigan Medical School
Emanuela Zuccaro: University of Padova
Mathilde Chivet: University of Trento
Cristina Mammucari: University of Padova
Marco Pacifici: University of Padova
Anna Raffaello: University of Padova
Rosario Rizzuto: University of Padova
Andrea Mattarei: University of Padova
Maria A. Desbats: University of Padova, and Fondazione Istituto di Ricerca Pediatrica Città della Speranza
Leonardo Salviati: University of Padova
Aram Megighian: University of Padova
Gianni Sorarù: Padova Neuroscience Center (PNC)
Elena Pegoraro: University of Padova
Elisa Belluzzi: University-Hospital of Padova
Assunta Pozzuoli: University-Hospital of Padova
Carlo Biz: University-Hospital of Padova
Pietro Ruggieri: University-Hospital of Padova
Chiara Romualdi: University of Padova
Andrew P. Lieberman: University of Michigan Medical School
Gopal J. Babu: New Jersey Medical School
Marco Sandri: University of Padova
Bert Blaauw: University of Padova
Manuela Basso: University of Trento
Maria Pennuto: University of Padova

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Deregulation of expression of ECC genes is concomitant with sexual maturity and androgen raise in the serum. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes. These observations show that ECC deregulation and defective mitochondrial respiration are early but reversible events followed by altered muscle force, calcium dyshomeostasis, and dismantling of triad structure.

Date: 2023
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DOI: 10.1038/s41467-023-36185-w

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