Skeletal Muscle Pathogenesis in Polyglutamine Diseases

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.

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

“…In the last decade, clinical and experimental evidence has established that skeletal muscle atrophy is not only secondary to MN dysfunction but also results from the primary cell-autonomous toxicity of polyQ-expanded AR in myofibers [8][9][10] . Patients show early muscle pathology and clear signs of myopathy, including elevated levels of serum creatine kinase, myofiber degeneration, and central-core-like areas without mitochondria; all of these changes are detected before or at the onset of clinical symptoms [11][12][13][14] .…”