title: Combined Strategies for Maintaining Skeletal Muscle Mass and Function in Aging: Myostatin Inactivation and AICAR-Associated Oxidative Metabolism Induction.
abstract: Myostatin (mstn) blockade, resulting in muscle hypertrophy, is a promising therapy to counteract age-related muscle loss. However, oxidative and mitochondrial deficit observed in young mice with myostatin inhibition could be detrimental with aging. The aim of this study was (a) to bring original data on metabolic and mitochondrial consequences of mstn inhibition in old mice, and (b) to examine whether 4-weeks of AICAR treatment, a pharmacological compound known to upregulate oxidative metabolism, may be useful to improve exercise capacity and mitochondrial deficit of 20-months mstn KO versus wild-type (WT) mice. Our results show that despite the enlarged muscle mass, the oxidative and mitochondrial deficit associated with reduced endurance running capacity is maintained in old mstn KO mice but not worsened by aging. Importantly, AICAR treatment induced a significant beneficial effect on running limit time only in old mstn KO mice, with a marked increase in PGC-1α expression and slight beneficial effects on mitochondrial function. We showed that AICAR effects were autophagy-independent. This study underlines the relevance of aged muscle remodelling by complementary approaches that impact both muscle mass and function, and suggest that mstn inhibition and aerobic metabolism activators should be co-developed for delaying age-related deficits in skeletal muscle.
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France INSERM U1046, Physiology and Experimental Medicine Heart-Muscle Unit, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Pauly
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Chabi
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: François Bertrand
authors.initials: FB
authors.lastname: Favier
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Frankie
authors.initials: F
authors.lastname: Vanterpool
authors.affiliation: INSERM U1046, Physiology and Experimental Medicine Heart-Muscle Unit, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
authors.forename: Stefan
authors.initials: S
authors.lastname: Matecki
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Fouret
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bonafos
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vernus
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Feillet-Coudray
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Coudray
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bonnieu
authors.affiliation: INRA, UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, F-34060, Montpellier, France christelle.ramonatxo@univ-montp1.fr.
authors.forename: Christelle
authors.initials: C
authors.lastname: Ramonatxo
mesh_terms: D000375:Aging; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D018955:CD36 Antigens / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006984:Hypertrophy; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin / Q000172:deficiency* / Q000235:genetics; D009929:Organ Size; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D016601:RNA-Binding Proteins / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000620:Aminoimidazole Carboxamide; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D018955:CD36 Antigens; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D008869:Microtubule-Associated Proteins; D055435:Myostatin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D012265:Ribonucleotides; D014157:Transcription Factors; C115010:Becn1 protein, mouse; C526109:Anxa3 protein, rat; C525912:Mstn protein, mouse; C118585:P62 protein, human; C485290:Ppargc1a protein, mouse; C495693:Slc2a4 protein, mouse; C031143:AICA ribonucleotide
keywords: AMPK; Autophagy; Endurance; Mitochondrial function; PGC-1α