title: Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways.
abstract: Skeletal muscle regrowth after atrophy is impaired in the aged and in this study we hypothesized that this can be explained by a blunted response of signaling pathways and cellular processes during reloading after hind limb suspension in muscles from old rats. Male Brown Norway Fisher 344 rats at 6 (young) and 32 (old) months of age were subjected to normal ambulatory conditions (amb), hind limb suspension for 14 days (HS), and HS followed by reloading through normal ambulation for 14 days (RE); soleus muscles were used for analysis of intracellular signaling pathways and cellular processes. Soleus muscle regrowth was blunted in old compared to young rats which coincided with a recovery of serum IGF-1 and IGFBP-3 levels in young but not old. However, the response to reloading for p-Akt, p-p70s6k and p-GSK3β protein abundance was similar between muscles from young and old rats, even though main effects for age indicate an increase in activation of this protein synthesis pathway in the aged. Similarly, MAFbx mRNA levels in soleus muscle from old rats recovered to the same extent as in the young, while Murf-1 was unchanged. mRNA abundance of autophagy markers Atg5 and Atg7 showed an identical response in muscle from old compared to young rats, but beclin did not. Autophagic flux was not changed at either age at the measured time point. Apoptosis was elevated in soleus muscle from old rats particularly with HS, but recovered in HSRE and these changes were not associated with differences in caspase-3, -8 or -9 activity in any group. Protein abundance of apoptosis repressor with caspase-recruitment domain (ARC), cytosolic EndoG, as well as cytosolic and nuclear apoptosis inducing factor (AIF) were lower in muscle from old rats, and there was no age-related difference in the response to atrophy or regrowth. Soleus muscles from old rats had a higher number of ED2 positive macrophages in all groups and these decreased with HS, but recovered in HSRE in the old, while no changes were observed in the young. Pro-inflammatory cytokines in serum did not show a differential response with age to different loading conditions. Results indicate that at the measured time point the impaired skeletal muscle regrowth after atrophy in aged animals is not associated with a general lack of responsiveness to changes in loading conditions.
authors: Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, 900 S Limestone, Lexington, KY 40536-0200, USA.
authors: Jena R
authors: JR
authors: White
authors: Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, 900 S Limestone, Lexington, KY 40536-0200, USA.
authors: Amy L
authors: AL
authors: Confides
authors: Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, 900 S Limestone, Lexington, KY 40536-0200, USA.
authors: Stephanie
authors: S
authors: Moore-Reed
authors: Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, 900 S Limestone, Lexington, KY 40536-0200, USA.
authors: Johanna M
authors: JM
authors: Hoch
authors: Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, 900 S Limestone, Lexington, KY 40536-0200, USA. Electronic address: eedupo2@uky.edu.
authors: Esther E
authors: EE
authors: Dupont-Versteegden
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D019417:Hindlimb Suspension; D007328:Insulin / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development*; D009133:Muscular Atrophy / Q000473:pathology*; D009929:Organ Size; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051033:Apoptosis Inducing Factor; D015415:Biomarkers; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D009124:Muscle Proteins; D007334:Insulin-Like Growth Factor I; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020169:Caspases
keywords: Apoptosis; Autophagy; Hind limb suspension; Inflammation; Protein degradation; Protein synthesis