The ubiquitin-proteasome and the mitochondria-associated apoptotic pathways are sequentially downregulated during recovery after immobilization-induced muscle atrophy.
Immobilization produces morphological, physiological, and biochemical alterations in skeletal muscle leading to muscle atrophy and long periods of recovery. Muscle atrophy during disuse results from an imbalance between protein synthesis and proteolysis but also between apoptosis and regeneration processes. This work aimed to characterize the mechanisms underlying muscle atrophy and recovery following immobilization by studying the regulation of the mitochondria-associated apoptotic and the ubiquitin-proteasome-dependent proteolytic pathways. Animals were subjected to hindlimb immobilization for 4-8 days (I4 to I8) and allowed to recover after cast removal for 10-40 days (R10 to R40). Soleus and gastrocnemius muscles atrophied from I4 to I8 to a greater extent than extensor digitorum longus and tibialis anterior muscles. Gastrocnemius muscle atrophy was first stabilized at R10 before being progressively reduced until R40. Polyubiquitinated proteins accumulated from I4, whereas the increased ubiquitination rates and chymotrypsin-like activity of the proteasome were detectable from I6 to I8. Apoptosome and caspase-3 or -9 activities increased at I6 and I8, respectively. The ubiquitin-proteasome-dependent pathway was normalized early when muscle stops to atrophy (R10). By contrast, the mitochondria-associated apoptotic pathway was first downregulated below basal levels when muscle started to recover at R15 and completely normalized at R20. Myf 5 protein levels decreased from I4 to I8 and were normalized at R10. Altogether, our results suggest a two-stage process in which the ubiquitin-proteasome pathway is rapidly up- and downregulated when muscle atrophies and recovers, respectively, whereas apoptotic processes may be involved in the late stages of atrophy and recovery.
Vazeille
Emilie
E
Unité de Nutrition Humaine, UMR1019, Institut National de la Recherche Agronomique, Saint Genes Champanelle, France.
Codran
Audrey
A
Claustre
Agnès
A
Averous
Julien
J
Listrat
Anne
A
Béchet
Daniel
D
Taillandier
Daniel
D
Dardevet
Dominique
D
Attaix
Didier
D
Combaret
Lydie
L
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053478:Apoptosomes / Q000378:metabolism*; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004435:Eating / Q000502:physiology; D019417:Hindlimb Suspension / Q000009:adverse effects; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
C506594:Apaf1 protein, rat; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D009124:Muscle Proteins; D051787:Myogenic Regulatory Factor 5; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex