Journal
JOURNAL OF APPLIED PHYSIOLOGY
Volume 104, Issue 1, Pages 27-33Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/japplphysiol.00736.2007
Keywords
muscle wasting; spinal cord injury; rehabilitation; AMP-activated protein kinase; Akt
Categories
Funding
- NHLBI NIH HHS [R01 HL-074122, R01 HL074122-04, R01 HL074122] Funding Source: Medline
- NIAMS NIH HHS [R01 AR049877-04, R01 AR-049877, R01 AR049877] Funding Source: Medline
- NIA NIH HHS [P30 AG024832] Funding Source: Medline
- NICHD NIH HHS [T32 HD007539-07, T32 HD007539] Funding Source: Medline
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [T32HD007539] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL074122] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR049877] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P30AG024832] Funding Source: NIH RePORTER
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Ribosomal S6 kinase 1 (S6K1) is a downstream component of the mammalian target of rapamycin (mTOR) signaling pathway and plays a regulatory role in translation initiation, protein synthesis, and muscle hypertrophy. AMP-activated protein kinase (AMPK) is a cellular energy sensor, a negative regulator of mTOR, and an inhibitor of protein synthesis. The purpose of this study was to determine whether the hypertrophy/cell growth-associated mTOR pathway was downregulated during muscle atrophy associated with chronic paraplegia. Soleus muscle was collected from male Sprague-Dawley rats 10 wk following complete T-4-T-5 spinal cord transection (paraplegic) and from sham-operated (control) rats. We utilized immunoprecipitation and Western blotting techniques to measure upstream [ AMPK, Akt/protein kinase B (PKB)] and downstream components of the mTOR signaling pathway [ mTOR, S6K1, SKAR, 4E-binding protein 1 (4EBP1), and eukaryotic initiation factor (eIF) 4G and 2 alpha]. Paraplegia was associated with significant soleus muscle atrophy (174 +/- 8 vs. 240 +/- 13 mg; P < 0.05). There was a reduction in phosphorylation of mTOR, S6K1, and eIF4G (P < 0.05) with no change in Akt/PKB or 4E-BP1 (P > 0.05). Total protein abundance of mTOR, S6K1, eIF2 alpha, and Akt/PKB was decreased, and increased for SKAR (P < 0.05), whereas 4E-BP1 and eIF4G did not change (P > 0.05). S6K1 activity was significantly reduced in the paraplegic group (P < 0.05); however, AMPK alpha 2 activity was not altered (3.5 +/- 0.4 vs. 3.7 +/- 0.5 pmol.mg(-1).min(-1), control vs. paraplegic rats). We conclude that paraplegia-induced muscle atrophy in rats is associated with a general downregulation of the mTOR signaling pathway. Therefore, in addition to upregulation of atrophy signaling during muscle wasting, downregulation of muscle cell growth/hypertrophy-associated signaling appears to be an important component of long-term muscle loss.
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