Changes in PKB/Akt and calcineurin signaling during recovery in atrophied soleus muscle induced by unloading

Hirosaki Gakuin University, Aomori, Aomori, Japan
AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.53). 06/2005; 288(5):R1273-8. DOI: 10.1152/ajpregu.00688.2004
Source: PubMed

ABSTRACT Protein kinase B [PKB, also known as Akt (PKB/Akt)] and calcineurin (CaN) are postulated to play important roles in integrating intracellular signaling in skeletal muscle in response to disuse and increased muscle loading. These experiments investigated changes in signal transduction of the downstream pathways of PKB/Akt and CaN during recovery following disuse-induced muscle atrophy. A 10-day period of hindlimb unloading (HLU) via tail suspension (male rats) was used to produce soleus muscle atrophy. Muscle recovery was achieved by returning animals to normal ambulation for 3-10 days. HLU resulted in significant muscle atrophy and a slow-to-fast fiber transition as revealed by appearance of type IId/x and IIb myosin heavy chain (MHC) isoforms. Muscle mass in HLU animals recovered to control (Con) levels after 10 days of reloading, but the fast-to-slow shift in muscle MHC was incomplete, as indicated by the continued presence of type IId/x MHC. Ten days of HLU resulted in a significant decrease (-43%) in muscle levels of phosphorylated PKB/Akt. In contrast, muscle levels of phosphorylated PKB/Akt were greater (+56%) in HLU than in Con animals early after the onset of reloading (3 days). Soleus levels of phosphorylated p70S6K were significantly higher (+26%) in HLU animals after 3 days of muscle reloading. Muscle levels of phosphorylated PKB/Akt and phosphorylated p70S6K returned to Con levels by day 10 of recovery. Moreover, muscle CaN levels were significantly higher than Con levels after 10 days of muscle reloading. These findings are consistent with the hypothesis that PKB/Akt and its downstream mediators are active in the regrowth of muscle mass during the early periods of recovery from muscle atrophy. Our data support the concept that CaN is involved in muscle remodeling during the later phases of recovery from disuse muscle atrophy.

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    ABSTRACT: Effects of mechanical loading on the expression level of tripartite motif-containing 72 (TRIM72) and caveolin-3 (Cav-3) in mouse soleus muscle were investigated. Mice were subjected to (1) continuous hindlimb suspension (HS) for 2 weeks followed by 1-week ambulation recovery or (2) functional overloading (FO) on the soleus by cutting the distal tendons of the plantaris and gastrocnemius muscles. Soleus muscle atrophy was induced by 2-week hindlimb suspension (HS). Reloading-associated regrowth of atrophied soleus muscle was observed by 1-week reloading following HS. HS also depressed the expression level of insulin receptor substrate-1 (IRS-1) mRNA, TRIM72, Cav-3, and phosphorylated Akt (p-Akt)/total Akt (t-Akt), but increased the phosphorylated level of p38 mitogen-activated protein kinase (p-p38MAPK) in soleus muscle. Thereafter, the expression level of MyoD mRNA, TRIM72 (mRNA, and protein), and Cav-3 was significantly increased and recovered to the basal level during 1-week reloading after HS. Although IRS-1 expression was also upregulated by reloading, the expression level was significantly lower than that before HS. Significant increase in p-Akt and phosphorylated p70 S6 kinase (p-p70S6K) was observed by 1-day reloading. On the other hand, 1-week functional overloading (FO) induced soleus muscle hypertrophy. In FO-associated hypertrophied soleus muscle, the expression level of IRS-1 mRNA, MyoD mRNA, TRIM72 mRNA, p-Akt, and p-p70S6K was increased, but the expression of Cav-3 and p-p38MAPK was decreased. FO had no effect on the protein expression level of TRIM72. These observations suggest that the loading-associated upregulation of TRIM72 protein in skeletal muscle may depress the regrowth of atrophied muscle via a partial suppression of IRS-1. In addition, downregulation of Cav-3 in skeletal muscle may depress overloading-induced muscle hypertrophy.
    12/2014; 2(12). DOI:10.14814/phy2.12259
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    ABSTRACT: Prolonged skeletal muscle inactivity causes muscle fiber atrophy. Redox imbalance has been considered one of the major triggers of skeletal muscle disuse atrophy, but it is still debated whether redox imbalance is actually the major cause or simply a consequence of muscle disuse. Here we hypothesized that a metabolic stress mediated by PGC-1α down-regulation plays a major role in disuse atrophy. First we studied the adaptations of soleus to mice hindlimb unloading (HU) in the early phase of disuse (3 and 7 days HU) with and without antioxidant treatment (trolox). HU caused reduction of cross sectional area, redox status alteration (NRF2, SOD1 and catalase up-regulation), and induction of the ubiquitin proteasome system (MuRF-1 and atrogin-1 mRNA up-regulation) and autophagy (Beclin1 and p62 mRNA up-regulation). Trolox completely prevented the induction of NRF2, SOD1 and catalase mRNAs, but not atrophy and catabolic systems induction in unloaded muscles, suggesting that oxidative stress is not a major cause of disuse atrophy. HU mice showed a marked alteration of oxidative metabolism. PGC-1α and mitochondrial complexes were down-regulated and DRP1 was up-regulated. To define the link between mitochondrial dysfunction and disuse muscle atrophy we unloaded mice overexpressing PGC-1α. Transgenic PGC-1α animals did not show metabolic alteration during unloading preserving muscle size through the reduction of autophagy and proteasome degradation. Our results indicate that mitochondrial dysfunction plays a major role in disuse atrophy and that compounds inducing PGC-1α expression could be useful to treat/prevent muscle atrophy.This article is protected by copyright. All rights reserved
    The Journal of Physiology 08/2014; 592(20). DOI:10.1113/jphysiol.2014.275545 · 4.54 Impact Factor
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