Gaugler M, Brown A, Merrell E, DiSanto-Rose M, Rathmacher JA, Reynolds TH 4th. PKB signaling and atrogene expression in skeletal muscle of aged mice. J Appl Physiol 111: 192-199, 2011. First published May 5, 2011 doi:10.1152/japplphysiol.00175.2011The purpose of this study was to determine if PKB signaling is decreased and contractile protein degradation is increased in extensor digitorum longus (EDL) and soleus (SOL) muscles from middle-aged (MA) and aged (AG) mice. We also examined the effect of age on atrogene expression in quadriceps muscle. PKB activity, as assessed by Thr 308 and Ser 473 phosphorylation, was significantly higher in EDL and SOL muscles from AG than MA mice. The age-related increase in PKB activity appears to be due to an increase in expression of the kinase, as PKB-␣ and PKB- levels were significantly higher in EDL and SOL muscles from AG than MA mice. The phosphorylation of forkhead box 3a (FOXO3a) on Thr 32 , a PKB target, was significantly higher in EDL muscles from AG than MA mice. The rate of contractile protein degradation was similar in EDL and SOL muscles from AG and MA mice. Atrogin-1 and muscle-specific RING finger protein 1 (MuRF-1) mRNA levels did not change in muscles from AG compared with MA mice, indicating that ubiquitin-proteasome proteolysis does not contribute to sarcopenia. A significant decrease in Bcl-2 and 19-kDa interacting protein 3 (Bnip3) and GABA receptor-associated protein 1 (Gabarap1) mRNA was observed in muscles from AG compared with MA mice, which may contribute to age-related contractile dysfunction. In conclusion, the mechanisms responsible for sarcopenia are distinct from experimental models of atrophy and do not involve atrogin-1 and MuRF-1 or enhanced proteolysis. Finally, a decline in autophagy-related gene expression may provide a novel mechanism for impaired contractile function and muscle metabolism with advancing age. signal transduction; atrophy; sarcopenia; proteolysis SARCOPENIA, THE AGE-RELATED loss of muscle mass, is present in ϳ45% of people Ն65 yr of age (14). Sarcopenia is a core component of a frailty syndrome that increases the risk of falling, reduces functional independence, and increases susceptibility to acute and chronic disease (9). In the United States, the direct healthcare costs associated with sarcopenia have been estimated to exceed $18 billion per year, an amount that is likely to increase dramatically because of the expansion of the aging population (14). The precise cause of sarcopenia is not established, but the condition is associated with physical inactivity, insulin resistance, nutritional deficiencies, elevated proinflammatory cytokines, and decreases in growth-promoting hormones.Ultimately, muscle size is determined by the relative rates of protein synthesis and degradation. Since the average protein turnover rate is ϳ4 -6 g protein·kg body wt Ϫ1 ·day Ϫ1 , or 280 g protein/day for a 70-kg adult (19), small persistent changes in the rates of protein synthesis or protein degradation could lead to substantial changes in ...
Reynolds 4th TH, Merrell E, Cinquino N, Gaugler M, Ng L. Disassociation of insulin action and Akt/FOXO signaling in skeletal muscle of older Akt-deficient mice.
The purpose of this study was to determine if sarcopenia is associated with insulin resistance, impaired AKT signaling, and increased contractile protein degradation rates. Insulin sensitivity was assessed by an insulin‐assisted glucose tolerance test (IAGTT) in middle‐aged (MA, 11–13 months) and aged (AG, 24–26 months) male C57B/6 mice. Contractile protein degradation rates were assessed by measuring 3‐methyl histidine release from isolated soleus (SOL) and extensor digitorum longus (EDL) muscles. During the IAGTT, blood glucose levels were significantly lower in AG mice compared to MA mice, indicating an improvement in insulin sensitivity with advancing age. The increase in insulin sensitivity observed in AG mice was associated with a significant increase in the phosphorylation of AKT in SOL and EDL muscles from AG compared to MA mice. The increase in AKT phosphorylation appears to be due to significant increases in both AKT1 and AKT2 expression. The phosphorylation of FOXO3a was significantly higher in EDL muscles from AG mice compared MA mice, but no age‐related differences in FOXO3a phosphorylation were observed in SOL muscles. The expression of the ubiquitin ligase, Atrogin‐1, was similar in SOL and EDL muscles from AG and MA mice. These results indicate that sarcopenia is not related to a decline in the ability of AKT to suppress Atrogin‐1 expression and contractile protein degradation.
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