The consequence of protein degradation exceeding protein synthesis is one of the main causes of skeletal muscle atrophy. This is the result of a grat number of reasons including conditions such as immobilization following traumatic lesions, deconditioning, ageing and in chronic diseases, so describing muscle atrophy as one of the major clinical problems. Papers concerning therapies for diminishing protein degradation of skeletal muscle atrophy are scarce and still under investigation. The concept of mitochondrial dysfunction is strictly associated with skeletal muscle atrophy and contributes to the induction of protein degradation and cell apoptosis. Basically, the failure in mitochondrial dynamics is believed to play a fundamental role in skeletal muscle atrophy. This mitochondrial status is thought to be closely related to a deficit of the level of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), a master regulator of mitochondrial biogenesis. The observation that overexpression of PGC1α blunted or prevented hindlimb unloading (HU) induced atrophy by counteracting activation of catabolic pathways in skeletal muscle of mice strengthened the idea that mitochondrial dysfunction plays a major role in disuse atrophy. There are few but encouraging evidence that exercise might be a tool to prevent disuse atrophy. Exercise is an attractive tool to prevent muscle wasting as it is known to cause mitochondrial adaptations and to enhance PCG1α expression. The mechanism of exercise-induced protection on muscle atrophy is not clearly defined yet. Here we investigate the morphological and molecular adaptation of Gastrocnemius muscle in response to hindlimb unloading with and without exercise preconditioning. Analyses focus on short duration, 3 days, hindlimb unloading since it has been shown to cause significant loss of Gastrocnemius mass by induction of atrogenes. The thesis discusses about mitochondrial adaptations and atrogenes expression responsible for exercise-induced protection from disuse skeletal muscle atrophy. We found that 7 days of endurance exercise before HU prevents Gastrocnemius muscle mass loss, impairment of mitochondrial dynamics and blunts a very early activation of a large set of FoxO dependent atrogenes.
L’eccessiva attivazione della degradazione proteica rispetto all’attività della sintesi proteica rappresenta la principale causa dell’atrofia muscolare da disuso. A determinare l’atrofia concorrono diverse condizioni come: immobilizzazione conseguente a lesioni traumatiche, decondizionamento, invecchiamento e malattie croniche, pertanto l’atrofia muscolare rappresenta un importante problema clinico. Attualmente i lavori scientifici mirati ad individuare terapie per controllare la degradazione proteica negli stati di atrofia muscolare sono numericamente pochi. Il concetto di disfunzione mitocondriale è strettamente associato all’atrofia muscolare e contribuisce all’induzione della degradazione proteica. Si ritiene che un deficit nei fenomeni di dinamica mitocondriale possa giocare un ruolo fondamentale nell’atrofia muscolare. Tale alterazione è spesso associata al deficit di PGC1α (peroxisome proliferator-activated receptor-γ coactivator-1α), un fattore di regolazione della biogenesi mitocondriale. Evidenze sperimentali hanno mostrato che l’overespressione di PGC1α in topi transgenici, protegge il muscolo dall’atrofia da disuso mediante l’inibizione dei processi di degradazione proteica rafforzando l’idea secondo cui la disfunzione mitocondriale gioca un ruolo fondamentale nell’atrofia da disuso. Poche ma incoraggianti evidenze scientifiche sottolineano come l’esercizio fisico potrebbe essere un interessante strumento per prevenire l’atrofia muscolare da disuso dal momento che è in grado di indurre un adattamento mitocondriale innalzando i livelli di espressione di PGC1α. A questo proposito, il meccanismo molecolare alla base della prevenzione non è ancora stato chiarito e definito. In questo studio è stato indagato l’adattamento morfologico e molecolare nel muscolo Gastrocnemio in risposta ad un periodo di disuso, indotto mediante il modello dell’hindlimb unloading, in presenza ed in assenza di precondizionamento fisico. Le analisi sono state concentrate sugli adattamenti muscolari conseguenti all’esposizione del muscolo a brevi periodi di disuso (3 giorni) dal momento che in questa fase del disuso è noto esserci atrofia del muscolo gastrocnemio associata ad induzione degli atrogeni. La tesi è dedicata agli adattamenti mitocondriali e all’espressione degli atrogeni, fattori potenzialmente responsabili del meccanismo di protezione dall’atrofia da disuso indotta dall’esercizio fisico. I risultati ottenuti indicano come 7 giorni di esercizio fisico prima dell’esposizione al protocollo di disuso (hindlimb unloading) prevengono la perdita di massa muscolare del Gastrocnemio, il deterioramento della dinamica mitocondriale e attenuano la precoce attivazione degli atrogeni FoXO dipendenti.
Endurance exercise preconditioning counteracts disuse skeletal muscle atrophy blunting atrogenes expression
MARZOLI, SALVATORE
2019/2020
Abstract
The consequence of protein degradation exceeding protein synthesis is one of the main causes of skeletal muscle atrophy. This is the result of a grat number of reasons including conditions such as immobilization following traumatic lesions, deconditioning, ageing and in chronic diseases, so describing muscle atrophy as one of the major clinical problems. Papers concerning therapies for diminishing protein degradation of skeletal muscle atrophy are scarce and still under investigation. The concept of mitochondrial dysfunction is strictly associated with skeletal muscle atrophy and contributes to the induction of protein degradation and cell apoptosis. Basically, the failure in mitochondrial dynamics is believed to play a fundamental role in skeletal muscle atrophy. This mitochondrial status is thought to be closely related to a deficit of the level of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), a master regulator of mitochondrial biogenesis. The observation that overexpression of PGC1α blunted or prevented hindlimb unloading (HU) induced atrophy by counteracting activation of catabolic pathways in skeletal muscle of mice strengthened the idea that mitochondrial dysfunction plays a major role in disuse atrophy. There are few but encouraging evidence that exercise might be a tool to prevent disuse atrophy. Exercise is an attractive tool to prevent muscle wasting as it is known to cause mitochondrial adaptations and to enhance PCG1α expression. The mechanism of exercise-induced protection on muscle atrophy is not clearly defined yet. Here we investigate the morphological and molecular adaptation of Gastrocnemius muscle in response to hindlimb unloading with and without exercise preconditioning. Analyses focus on short duration, 3 days, hindlimb unloading since it has been shown to cause significant loss of Gastrocnemius mass by induction of atrogenes. The thesis discusses about mitochondrial adaptations and atrogenes expression responsible for exercise-induced protection from disuse skeletal muscle atrophy. We found that 7 days of endurance exercise before HU prevents Gastrocnemius muscle mass loss, impairment of mitochondrial dynamics and blunts a very early activation of a large set of FoxO dependent atrogenes.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/12485