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Soleus and gastrocnemius tenotomy causes fiber type specific muscle atrophy in mouse tibialis anterior
Author(s) -
Bott Kirsten N.,
Watson Colton J.F.,
Leveille Cameron F.,
MacNeil Adam J.,
Peters Sandra J.,
LeBlanc Paul J.,
Fajardo Val Andrew
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.856.31
Subject(s) - tenotomy , atrophy , muscle atrophy , soleus muscle , muscle hypertrophy , tibialis anterior muscle , medicine , gastrocnemius muscle , endocrinology , anatomy , skeletal muscle , tendon
Examining the molecular mechanisms regulating muscle mass is critical in determining potential therapeutic strategies for preventing muscle loss in a variety of conditions. We have previously utilized a simultaneous muscle overload/unload model, whereby tenotomy of soleus and gastrocnemius tendons mechanically overloads plantaris leading to hypertrophy while unloading soleus leading to atrophy after two weeks. In this model, the foot of the tenotomized leg appears to be held in dorsiflexion, likely due to the loss of soleus and gastrocnemius muscle function, which synergistically act towards plantar flexion. Previous research has shown that dorsiflexion immobilization results in significant muscle atrophy of tibialis anterior (TA) due to an increase in inflammation and polyubiquitylation. Therefore, the present study examined whether TA muscles from the tenotimized leg would also display significant muscle atrophy, and whether increased inflammation and polyubiquitylation would contribute to the muscle loss. We also examined glycogen synthase kinase 3 (GSK3) activation, given this enzyme's role in promoting polyubiquitylation and muscle atrophy. Ten male C57BL/6N mice (28.1 ± 0.8g) were subjected to soleus and gastrocnemius tenotomy (TN) in one leg, while the other leg was subjected to a sham surgery to serve as an internal control (CON). Two‐weeks post‐surgery the mice were euthanized and the TA muscles were collected. On average, TA muscles in the TN leg were smaller compared to the CON leg (CON, 60.0 +/− 2.0 mg vs TNY 52.8 +/− 2.2 mg, p<0.01), suggesting muscle atrophy was occurring in the TN leg. Using immunofluorescent fiber typing, it was found that this was due to a selective reduction in myofiber cross‐sectional area of type IIB (CON 4091± 275 μm 2 vs. TN 3599± 193 μm 2 , p<0.01) and type IIX‐IIB (CON 3281± 243 μm 2 vs. TN 2933± 262 μm 2 , p<0.05), without any significant reductions in total number of myofibers or fiber type distribution. H&E staining showed some centralized nuclei with no signs of mononuclear cell infiltration in the TN TA. Correspondingly, no significant changes in mRNA expression of IL‐6 and TNFa inflammatory cytokines were observed in TN TA. However, we did observe a 1.9‐fold (p<0.05) increase in polyubiquitylated proteins and higher GSK3 activation as revealed by a 30% reduction in phosphorylated GSK3 (relative to total GSK3; p<0.05) in the TN TA compared to CON. In conclusion, TA muscle undergoes a selective atrophy of fast‐glycolytic fibers in response to soleus and gastrocnemius TN, and this may be due to GSK3 activation and polyubiquitylation. Future studies should investigate whether GSK3 represents a viable therapeutic target in this model. Support or Funding Information NSERC This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .