A Soluble Activin Receptor IIB Fails to Prevent Muscle Atrophy in a Mouse Model of Spinal Cord Injury

Abstract

Myostatin (MST) is a potent regulator of muscle growth and size. Spinal cord injury (SCI) results in marked atrophy of muscle below the level of injury. Currently, there is no effective pharmaceutical treatment available to prevent sublesional muscle atrophy post-SCI. To determine whether inhibition of MST with a soluble activin IIB receptor (RAP-031) prevents sublesional SCI-induced muscle atrophy, mice were randomly assigned to the following groups: Sham-SCI; SCI+Vehicle group (SCI-VEH); and SCI+RAP-031 (SCI-RAP-031). SCI was induced by complete transection at thoracic level 10. Animals were euthanized at 56 days post-surgery. RAP-031 reduced, but did not prevent, body weight loss post-SCI. RAP-031 increased total lean tissue mass compared to SCI-VEH (14.8%). RAP-031 increased forelimb muscle mass post-SCI by 38% and 19% for biceps and triceps, respectively (p < 0.001). There were no differences in hindlimb muscle weights between the RAP-031 and SCI-VEH groups. In the gastrocnemius, messenger RNA (mRNA) expression was elevated for interleukin (IL)-6 (8-fold), IL-1β (3-fold), and tumor necrosis factor alpha (8-fold) in the SCI-VEH, compared to the Sham group. Muscle RING finger protein 1 mRNA was 2-fold greater in the RAP-031 group, compared to Sham-SCI. RAP-031 did not influence cytokine expression. Bone mineral density of the distal femur and proximal tibia were decreased post-SCI (-26% and -28%, respectively) and were not altered by RAP-031. In conclusion, MST inhibition increased supralesional muscle mass, but did not prevent sublesional muscle or bone loss, or the inflammation in paralyzed muscle.

Contusion spinal cord injury upregulates p53 protein expression in rat soleus muscle at multiple timepoints but not key senescence cytokines

“…Elevated muscle inflammation is associated with aging, and primary cells isolated and cultured from vastus lateralis biopsies of aged individuals show greater downstream NF‐κB activation response to recombinant TNFα as well as blunted differentiation and fusion compared to young individuals (Merritt, Stec, & Thalacker‐Mercer, ). A complete spinal cord transection in female mice 8 weeks after the injury resulted in greater IL‐1β, IL‐6, and TNFα mRNA expression in paralyzed gastrocnemius muscles (Graham et al, ). Chronic SCI has also resulted in greater vastus lateralis expression of the pro‐atrophy inflammatory regulators Fn14 (TWEAK receptor) and TNFα receptor 1B in humans, although there were no changes in the mRNA expression of IL‐6, TNFα, or TWEAK.…”

“…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, ), 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, ). This study did not determine which population of cells in the lysate were responsible for the changes in gene expression but does provide some insight that paralysis may affect or induce the expression of genes associated with SASP.…”

Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives

“…22,30,39,40 MSTN was implicated as a key regulator of muscle health after SCI using rat and mouse models. 43 The mice given the MSTN inhibitor had greater upper limb muscle masses but, interestingly, paralysed muscle mass was unaffected by the MSTN inhibitor. 41 In a separate study, the miRNA profile of whole gastrocnemius homogenates after SCI-induced muscle paralysis was associated with TGFβ family signalling by bioinformatics analysis as dysregulated miRNAs target multiple components of myostatin signalling.…”

“…37,38 The regulation of MSTN and its function in the control of muscle mass have been studied in detail. 43 The MSTN inhibitor reduced the amount of body mass lost compared to vehicle-treated animals over 8 weeks post-SCI. 10 In a rat model of complete SCI, expression of MSTN mRNA was not increased in whole muscle homogenate, but there was elevated ActRIIB mRNA expression and increased nuclear localization of the SMAD2/3, suggesting greater sensitivity to MSTN after SCI.…”

“…10 In a rat model of complete SCI, expression of MSTN mRNA was not increased in whole muscle homogenate, but there was elevated ActRIIB mRNA expression and increased nuclear localization of the SMAD2/3, suggesting greater sensitivity to MSTN after SCI. 43 These findings suggest the inhibition of MSTN may need to be used in conjunction with inhibitors of other signals of atrophy to prevent the loss of skeletal muscle which occurs with SCI-induced muscle paralysis. 42 Another study investigated the effects of inhibition of MSTN with a soluble ActRIIB receptor after a complete SCI in mice.…”