BNIP3
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [NIP3]
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Intrinsic exercise capacity is predictive of both lifespan and healthspan but whether adaptive exercise capacity influences the benefits achieved from aerobic training implemented later in life is not known. To determine if exercise late in life provides any functional improvements or underlying beneficial biochemical adaptations in rats bred to have a high response to training (HRT rats) or little to no response to training (LRT rats). Adult (11 months) and old (22 months) female LRT and HRT rats either remained sedentary (SED) or were exercised (EXER) on a treadmill 2-3 times/week at 60% of their initial maximum running speed and distance for 4 months. At 26 months of age, exercise capacity was re-evaluated and extensor digitorum longus, gastrocnemius (GTN), and tibialis anterior (TA) muscles were excised for histological and biochemical analysis. Both SED-HRT and SED-LRT rats showed decreased exercise capacity from 22 to 26 months, but with 4 months of treadmill training, EXER-HRT rats displayed a 50% improvement in exercise capacity while EXER-LRT rats maintained pre-training levels. Protein levels of antioxidant enzymes PRDX3, CuZnSOD, and PRXV were 6-fold greater in TA muscles of aged HRT rats compared to LRT rats. PGC-1α protein levels were ~2-fold greater in GTN and TA muscles of aged HRT than in LRT rats and TFAM protein was similarly elevated in GTN muscles of aged HRT rats compared with LRT rats. BNIP3 protein levels were 5-fold greater in TA muscles of aged HRT than in LRT rats while PINK1 protein content was reduced by 78% in GTN muscles of aged HRT rats compared with LRT rats. HRT rats retained the ability to improve exercise capacity into late life and that ability was associated with inherent and adaptive changes in antioxidant enzyme levels and markers of and mitochondrial quality related to healthspan benefits in aging. Moreover, low intensity exercise prevented the age-associated decline in functional exercise capacity in LRT rats.
MeSH Terms
- Adaptation, Physiological
- Animals
- Antioxidants
- Exercise Tolerance
- Female
- Longevity
- Male
- Mitochondrial Proteins
- Muscle, Skeletal
- Physical Conditioning, Animal
- Rats
Keywords
- Aging
- Antioxidant enzymes
- Mitochondrial biogenesis
- Nonresponders
- Skeletal muscle
Exercise training has been reported to prevent the age-induced decline in muscle mass and fragmentation of mitochondria, as well as to affect autophagy and mitophagy. The interaction between these pathways during aging as well as the similarity between such changes in human and mouse skeletal muscle is however not fully understood. Therefore the aim of the present study was to test the hypothesis that cellular degradation pathways, including apoptosis, autophagy and mitophagy are coordinately regulated in mouse and human skeletal muscle during aging and lifelong exercise training through a PGC-1α-p53 axis. Muscle samples were obtained from young untrained, aged untrained and aged lifelong exercise trained men, and from whole-body PGC-1α knockout mice and their littermate controls that were either lifelong exercise trained or sedentary young and aged. Lifelong exercise training prevented the aging-induced reduction in PGC-1α, p53 and p21 mRNA as well as the increase in LC3II and BNIP3 protein in mouse skeletal muscle, while aging decreased the BAX/Bcl-2 ratio, LC3I and BAX protein in mouse skeletal muscle without effects of lifelong exercise training. In humans, aging was associated with reduced PGC-1α mRNA as well as decreased p62 and p21 protein in skeletal muscle, while lifelong exercise training increased BNIP3 protein and decreased p53 mRNA. In conclusion, there was a divergent regulation of autophagy and apoptosis in mouse muscle with aging and lifelong exercise training, whereas healthy aged human skeletal muscle seemed rather robust to changes in apoptosis, autophagy and mitophagy markers compared with mouse muscle at the investigated age.
MeSH Terms
- Adult
- Aging
- Animals
- Apoptosis
- Autophagy
- Autophagy-Related Proteins
- Exercise
- Female
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Mitochondria
- Muscle, Skeletal
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Physical Conditioning, Animal
- RNA, Messenger
- Transcription Factors
- Young Adult
Keywords
- Aging
- Apoptosis
- Autophagy
- Lifelong exercise training
- PGC-1α
- Skeletal muscle
- p53
Loss of muscle mass during periods of disuse likely has negative health consequences for older adults. We have previously shown that β-hydroxy-β-methylbutyrate (HMB) supplementation during 10 days of strict bed rest (BR) attenuates the loss of lean mass in older adults. To elucidate potential molecular mechanisms of HMB effects on muscle during BR and resistance training rehabilitation (RT), we examined mediators of skeletal muscle mitochondrial dynamics, autophagy and atrophy, and intramyocellular lipids. Nineteen older adults (60-76 yr) completed 10 days BR followed by 8-wk RT rehabilitation. Subjects were randomized to either HMB (3 g/day HMB; [i]n[/i] = 11) or control (CON; [i]n[/i] = 8) groups. Skeletal muscle cross-sectional area (CSA) was determined by histology from percutaneous vastus lateralis biopsies. We measured protein markers of mitochondrial content [oxidative phosphorylation (OXPHOS)], fusion and fission (MFN2, OPA1, FIS1, and DRP1), autophagy (Beclin1, LC3B, and BNIP3), and atrophy [poly-ubiquinated proteins (poly-ub)] by Western blot. Fatty acid composition of several lipid classes in skeletal muscle was measured by infusion-MS analysis. Poly-ub proteins and OXPHOS complex I increased in both groups following BR ([i]P[/i] < 0.05, main effect for time), and muscle triglyceride content tended to increase following BR in the HMB group ([i]P[/i] = 0.055). RT rehabilitation increased OXPHOS complex II protein ([i]P[/i] < 0.05), and total OXPHOS content tended ([i]P[/i] = 0.0504) to be higher in HMB group. In addition, higher levels of DRP1 and MFN2 were maintained in the HMB group after RT ([i]P[/i] < 0.05). BNIP3 and poly-ub proteins were significantly reduced following rehabilitation in both groups ([i]P[/i] < 0.05). Collectively, these data suggest that HMB influences mitochondrial dynamics and lipid metabolism during disuse atrophy and rehabilitation. Mitochondrial content and dynamics remained unchanged over 10 days of BR in older adults. HMB stimulated intramuscular lipid storage as triacylglycerol following 10 days of bed rest (BR) and maintained higher mitochondrial OXPHOS content and dynamics during the 8-wk resistance exercise rehabilitation program.
MeSH Terms
- Age Factors
- Aged
- Autophagy
- Bed Rest
- Double-Blind Method
- Energy Metabolism
- Female
- Humans
- Lipid Metabolism
- Male
- Middle Aged
- Mitochondria, Muscle
- Mitochondrial Dynamics
- Mitochondrial Proteins
- Prospective Studies
- Proteolysis
- Quadriceps Muscle
- Resistance Training
- Sarcopenia
- Signal Transduction
- Time Factors
- Treatment Outcome
- Valerates
Keywords
- HMB
- aging
- bed rest
- exercise
- mitochondria
Aging is accompanied with unfavorable geometric and functional changes in the heart involving dysregulation of Akt and autophagy. This study examined the impact of Akt2 ablation on life span and cardiac aging as well as the mechanisms involved with a focus on autophagy and mitochondrial integrity. Cardiac geometry, contractile, and intracellular Ca properties were evaluated using echocardiography, IonOptix edge-detection and fura-2 techniques. Levels of Sirt1, mitochondrial integrity, autophagy, and mitophagy markers were evaluated using Western blot. Our results revealed that Akt2 ablation prolonged life span (by 9.1%) and alleviated aging (24 months)-induced unfavorable changes in myocardial function and intracellular Ca handling (SERCA2a oxidation) albeit with more pronounced cardiac hypertrophy (58.1%, 47.8%, and 14.5% rises in heart weight, wall thickness, and cardiomyocyte cross-sectional area). Aging downregulated levels of Sirt1, increased phosphorylation of Akt, and the nuclear transcriptional factor Foxo1, as well as facilitated acetylation of Foxo1, the effects of which (except Sirt1 and Foxo1 acetylation) were significantly attenuated or negated by Akt2 ablation. Advanced aging disturbed autophagy, mitophagy, and mitochondrial integrity as evidenced by increased p62, decreased levels of beclin-1, Atg7, LC3B, BNIP3, PTEN-induced putative kinase 1 (PINK1), Parkin, UCP-2, PGC-1α, and aconitase activity, the effects of which were reversed by Akt2 ablation. Aging-induced cardiomyocyte contractile dysfunction and loss of mitophagy were improved by rapamycin and the Sirt1 activator SRT1720. Activation of Akt using insulin or Parkin deficiency prevented SRT1720-induced beneficial effects against aging. In conclusion, our data indicate that Akt2 ablation protects against cardiac aging through restored Foxo1-related autophagy and mitochondrial integrity.
MeSH Terms
- Adaptation, Physiological
- Animals
- Atrial Remodeling
- Autophagy
- Autophagy-Related Protein 7
- Beclin-1
- Calcium
- Cardiomegaly
- Forkhead Box Protein O1
- Gene Expression Regulation
- Heterocyclic Compounds, 4 or More Rings
- Longevity
- Male
- Membrane Proteins
- Mice
- Mice, Knockout
- Microtubule-Associated Proteins
- Mitochondria
- Mitochondrial Proteins
- Myocardial Contraction
- Myocardium
- Phosphorylation
- Protein Kinases
- Proto-Oncogene Proteins c-akt
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
- Signal Transduction
- Sirolimus
- Sirtuin 1
Keywords
- Akt
- aging
- autophagy
- cardiac geometry
- contractile function
{{medline-entry |title=In Brief: Mitophagy: mechanisms and role in human disease. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27453450 |abstract=Mitophagy is a selective form of macro-autophagy in which mitochondria are specifically targeted for autophagic degradation. Mitophagy plays an important role in cellular homeostasis by eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to stress. Cells execute mitophagy through several non-redundant mechanisms, including the PINK1/Parkin partnership, which modulates turnover of depolarized mitochondria, and stress-induced BNIP3, NIX, and FUNDC1 molecular adaptors, which interact directly with LC3 to promote mitophagy. These pathways are deregulated in human diseases, including cancer, neurodegeneration, metabolic disorders, muscle atrophy, ageing, and inflammation, reflecting the importance of mitophagy as a cellular housekeeping function. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley