title: Evidence for caspase-dependent programmed cell death along with repair processes in affected skeletal muscle fibres in patients with mitochondrial disorders.
abstract: Mitochondrial disorders are heterogeneous multisystemic disorders due to impaired oxidative phosphorylation causing defective mitochondrial energy production. Common histological hallmarks of mitochondrial disorders are RRFs (ragged red fibres), muscle fibres with abnormal focal accumulations of mitochondria. In contrast with the growing understanding of the genetic basis of mitochondrial disorders, the fate of phenotypically affected muscle fibres remains largely unknown. We investigated PCD (programmed cell death) in muscle of 17 patients with mitochondrial respiratory chain dysfunction. We documented that in affected muscle fibres, nuclear chromatin is condensed in lumpy irregular masses and cytochrome c is released into the cytosol to activate, along with Apaf-1 (apoptotic protease-activating factor 1), caspase 9 that, in turn, activates effector caspase 3, caspase 6, and caspase 7, suggesting the execution of the intrinsic apoptotic pathway. Whereas active caspase 3 underwent nuclear translocation, AIF (apoptosis-inducing factor) mainly stayed within mitochondria, into which an up-regulated Bax is relocated. The significant increase in caspase 2, caspase 3 and caspase 6 activity strongly suggest that the cell death programme is caspase-dependent and the activation of caspase 2 together with PUMA (p53 up-regulated modulator of apoptosis) up-regulation point to a role for oxidative stress in triggering the intrinsic pathway. Concurrently, in muscle of patients, the number of satellite cells was significantly increased and myonuclei were detected at different stages of myogenic differentiation, indicating that a reparative programme is ongoing in muscle of patients with mitochondrial disorders. Together, these data suggest that, in patients with mitochondrial disorders, affected muscle fibres are trapped in a mitochondria-regulated caspase-dependent PCD while repairing events take place.
authors.affiliation: Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Guglielmi
authors.affiliation: Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy gaetano.vattemi@univr.it.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Vattemi
authors.affiliation: Department of Biotechnology, University of Verona, 37134 Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chignola
authors.affiliation: Department of Life and Reproduction Sciences, Section of Histology and Embryology, University of Verona, 37134 Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Chiarini
authors.affiliation: Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marini
authors.affiliation: Department of Life and Reproduction Sciences, Section of Histology and Embryology, University of Verona, 37134 Verona, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dal Prà
authors.affiliation: Department of Public Health and Community Medicine, Section of Pharmacology, University of Verona, 37134 Verona, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Di Chio
authors.affiliation: Department of Public Health and Community Medicine, Section of Pharmacology, University of Verona, 37134 Verona, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Chiamulera
authors.affiliation: Department of Life and Reproduction Sciences, Section of Histology and Embryology, University of Verona, 37134 Verona, Italy.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Armato
authors.affiliation: Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
mesh_terms: D017209:Apoptosis; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism*; D006801:Humans; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000503:physiopathology*; D018485:Muscle Fibers, Skeletal / Q000502:physiology*
chemical_list: D020169:Caspases
keywords: apoptosis; caspases; mitochondrial disorders; programmed cell death; satellite cells