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: Marion Pauly, Béatrice Chabi, François Bertrand Favier, Frankie Vanterpool, Stefan Matecki, Gilles Fouret, Béatrice Bonafos, Barbara Vernus, Christine Feillet-Coudray, Charles Coudray, Anne Bonnieu, Christelle Ramonatxo
• Journal: The journals of gerontology. Series A, Biological sciences and medical sciences (J Gerontol A Biol Sci Med Sci) Vol. 70 Issue 9 Pg. 1077-87 (Sep 2015) ISSN: 1758-535X [Electronic] United States
• PMID: 25227129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Apoptosis Regulatory Proteins
• Beclin-1
• Becn1 protein, mouse
• CD36 Antigens
• Glucose Transporter Type 4
• Hypoglycemic Agents
• LC3 protein, rat
• Microtubule-Associated Proteins
• Mstn protein, mouse
• Myostatin
• P62 protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• RNA-Binding Proteins
• Ribonucleotides
• Slc2a4 protein, mouse
• Transcription Factors
• Aminoimidazole Carboxamide
• AICA ribonucleotide

Topics

• Aging
• Aminoimidazole Carboxamide (analogs & derivatives, pharmacology)
• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy
• Beclin-1
• CD36 Antigens (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Hypertrophy
• Hypoglycemic Agents (pharmacology)
• Male
• Mice, Knockout
• Microtubule-Associated Proteins (metabolism)
• Mitochondria, Muscle (metabolism)
• Muscle, Skeletal (metabolism, pathology)
• Myostatin (deficiency, genetics)
• Organ Size
• Oxygen Consumption
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Physical Conditioning, Animal
• Physical Endurance
• RNA-Binding Proteins (metabolism)
• Ribonucleotides (pharmacology)
• Transcription Factors (metabolism)