Abstract
To determine whether muscle disuse after a spinal cord injury (SCI) produces elevated markers of cellular senescence and induces markers of the senescence‐associated secretory phenotypes (SASPs) in paralyzed skeletal muscle. Four‐month‐old male Sprague‐Dawley rats received a moderate‐severe (250 kiloDyne) T‐9 contusion SCI or Sham surgery and were monitored over 2 weeks, and 1‐, 2‐, or 3 months. Animals were sacrificed via isoflurane overdose and terminal exsanguination and the soleus was carefully excised and snap frozen. Protein expression of senescence markers p53, p27, and p16 was determined from whole soleus lysates using Western immunoblotting and RT‐qPCR was used to determine the soleus gene expression of IL‐1α, IL‐1β, IL‐6, CXCL1, and TNFα. SCI soleus muscle displayed 2‐ to 3‐fold higher total p53 protein expression at 2 weeks, and at 1 and 2 months when compared with Sham. p27 expression was stable across all groups and timepoints. p16 protein expression was lower at 3 months in SCI versus Sham, but not earlier timepoints. Gene expression was relatively stable between groups at 2 weeks. There were Surgery x Time interaction effects for IL‐6 and TNFα mRNA expression but not for IL‐1α, IL‐1β, or CXCL1. There were no main effects for time or surgery for IL‐1α, IL‐1β, or CXCL1, but targeted t tests showed reductions in IL‐1α and CXCL1 in SCI animals compared to Sham at 3 months and IL‐1β was reduced in SCI animals compared to Sham animals at the 2‐month timepoint. The elevation in p53 does not appear consistent with the induction of SASP because mRNA expression of cytokines associated with senescence was not uniformly upregulated and, in some instances, was downregulated in the early chronic phase of SCI.
Highlights
Spinal cord injury (SCI) is associated with severe reductions in the health of the musculoskeletal system due to disuse and immobilization below the spinal lesion
Cellular senescence is a remodeling process in which cells exit the proliferative stage of the cell cycle and signal for immune clearance using the senescence-associated secretory phenotype (SASP), an event which involves the release of cytokines, chemokines, and other molecules required for cellular breakdown (Munoz-Espin & Serrano, 2014)
Because muscle atrophy is a major consequence of muscle mass loss after SCI and reduced satellite cell numbers have been reported in individuals with SCI compared to able-bodied controls (Verdijk et al, 2012), skeletal muscle itself or inflammatory cell infiltration may be responsible for any elevations in SASP
Summary
Spinal cord injury (SCI) is associated with severe reductions in the health of the musculoskeletal system due to disuse and immobilization below the spinal lesion. The extensive muscle atrophy (Qin, Bauman, & Cardozo, 2010) that occurs after SCI is associated with reductions in systemic glucose handling and elevated rates for developing type II diabetes mellitus and cardiovascular diseases (Bauman & Spungen, 2001; Gorgey et al, 2014), outcomes linked with the accumulation of visceral fat tissue (Cirnigliaro et al, 2015) and a potential rise in systemic pro-inflammatory cytokines (Rosen & Spiegelman, 2014). Because muscle atrophy is a major consequence of muscle mass loss after SCI and reduced satellite cell numbers have been reported in individuals with SCI compared to able-bodied controls (Verdijk et al, 2012), skeletal muscle itself or inflammatory cell infiltration may be responsible for any elevations in SASP. We have shown a complete spinal cord transection results in elevations in pro-inflammatory cytokine gene expression in paralyzed whole muscle lysates 56 days after SCI compared to Sham controls (Graham, Harlow, & Peng, 2015).
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