Citation: Marchioretti, C.; Zuccaro, E.; Pandey, U.B.; Rosati, J.; Basso, M.; Pennuto, M. Skeletal Muscle Pathogenesis in Polyglutamine Diseases. Cells 2022, 11, 2105. https://doi.org/10.3390/ cells11132105 Academic Editor: Basil J. Petrof Received: 19 May 2022 Accepted: 28 June 2022 Published: 3 July 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Review Skeletal Muscle Pathogenesis in Polyglutamine Diseases Caterina Marchioretti 1,2,† , Emanuela Zuccaro 1,2,† , Udai Bhan Pandey 3 , Jessica Rosati 4 , Manuela Basso 5 and Maria Pennuto 1,2, * 1 Department of Biomedical Sciences (DBS), University of Padova, 35131 Padova, Italy; caterina.marchioretti@unipd.it (C.M.); emanuela.zuccaro@unipd.it (E.Z.) 2 Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy 3 Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15100, USA; udai@pitt.edu 4 Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71100 Foggia, Italy; j.rosati@css-mendel.it 5 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38100 Trento, Italy; manuela.basso@unitn.it * Correspondence: maria.pennuto@unipd.it † These authors contributed equally to this work. Abstract: Polyglutamine diseases are characterized by selective dysfunction and degeneration of specific types of neurons in the central nervous system. In addition, nonneuronal cells can also be affected as a consequence of primary degeneration or due to neuronal dysfunction. Skeletal muscle is a primary site of toxicity of polyglutamine-expanded androgen receptor, but it is also affected in other polyglutamine diseases, more likely due to neuronal dysfunction and death. Nonetheless, pathological processes occurring in skeletal muscle atrophy impact the entire body metabolism, thus actively contributing to the inexorable progression towards the late and final stages of disease. Skeletal muscle atrophy is well recapitulated in animal models of polyglutamine disease. In this review, we discuss the impact and relevance of skeletal muscle in patients affected by polyglutamine diseases and we review evidence obtained in animal models and patient-derived cells modeling skeletal muscle. Keywords: Huntington’s disease; spinal and bulbar muscular atrophy; spinocerebellar ataxia; skeletal muscle atrophy; polyglutamine diseases 1. Introduction Polyglutamine diseases are a family of nine neurodegenerative diseases that includes spinal and bulbar muscular atrophy (SBMA); Huntington’s disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, and 17 [1,2] (Figure 1, Table 1). Polyglutamine diseases are caused by expansions of the cytosine- adenine-guanine (CAG) trinucleotide repeat in the exons of specific genes. These genes code for unrelated proteins, that is, androgen receptor (AR), huntingtin (HTT), atrophin-1, ataxin-1, ataxin-2, ataxin-3, α1a-subunit of the P/Q voltage-dependent calcium channel (CACNA1A), ataxin-7, and the TATA-box binding protein (TBP). CAG expansions result in the production of proteins with aberrantly expanded polyglutamine tracts. All polyglu- tamine diseases are autosomal dominant, except SBMA, which is X-linked. Polyglutamine diseases belong to the family of brain misfolding diseases, which are a large group of neurodegenerative disorders that also includes Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and many others [3]. Brain misfolding diseases repre- sent a major health burden for the entire world with an estimated number of more than 30 million patients in the next 50 years [4,5]. Brain misfolding diseases share several com- monalities, such as being late-onset and progressive diseases. Symptoms typically manifest around the third to fifth decade of life, except for the juvenile forms observed in patients Cells 2022, 11, 2105. https://doi.org/10.3390/cells11132105 https://www.mdpi.com/journal/cells