The ketogenic diet preserves skeletal muscle with aging in mice

• Published in: Aging cell 2021-04, Vol.20 (4), p.e13322-n/a
• Main Authors: Wallace, Marita A., Aguirre, Nicholas W., Marcotte, George R., Marshall, Andrea G., Baehr, Leslie M., Hughes, David C., Hamilton, Karyn L., Roberts, Megan N., Lopez‐Dominguez, Jose Alberto, Miller, Benjamin F., Ramsey, Jon J., Baar, Keith
• Format: Article
• Language: English
• Subjects: Adaptation; Age; Aging; Aging - physiology; Animals; Antioxidants; Antioxidants - metabolism; Biosynthesis; Diet; Diet, Ketogenic - methods; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Genotype & phenotype; Growth factors; High fat diet; Inflammation; Insulin; Ketogenesis; ketogenic diet; Life span; Low carbohydrate diet; Male; Malnutrition; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria, Muscle - metabolism; Molecular modelling; Muscle, Skeletal - metabolism; Musculoskeletal system; Neuromuscular Junction - metabolism; Neuromuscular junctions; Nutrient deficiency; Nutrition; Organelle Biogenesis; Original Paper; Original Papers; Oxidation-Reduction; Oxidative metabolism; Oxidative stress; Oxidative Stress - physiology; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein biosynthesis; Protein Biosynthesis - physiology; Protein turnover; Proteins; Sarcopenia; Sarcopenia - diet therapy; Sarcopenia - metabolism; Signal Transduction - physiology; Skeletal muscle
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13322

The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve‐month‐old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long‐term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age. Nutrition interventions impact the preservation of skeletal muscle mass and function with age. This study demonstrated that the ketogenic diet (KD) improved skeletal muscle mass preservation with age. As muscle progresses from adult to old, individuals on a standard control (CON) diet show less reinnervation and more unfolded proteins. By contrast, individuals on a long‐term KD showed more mitochondria, greater reinnervation, more oxidative muscle fibers, and decreased translation initiation.