Intrinsic contractile dysfunction in a surgical model of muscle hypertrophy: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle

Synergistic ablation (SA) is widely used to induce muscle hypertrophy in rodent studies. However, it has been demonstrated that SA-induced compensatory hypertrophy induces increases in maximum isometric force that are smaller in magnitude than the increase in muscle cross-sectional area, suggesting a reduction in the specific force production due to intrinsic contractile dysfunction in the hypertrophied fibers. Here, by using the mechanical skinned fibers, we investigated the mechanisms behind the reduction in specific force in the compensatory hypertrophied muscles. Rats had unilateral surgical ablation of the gastrocnemius and soleus muscles to induce the compensatory hypertrophy in the plantaris muscles. Two wk after surgery, the mean fiber diameter was increased by 19% in the SA group compared with the contralateral control (CNT) group. In contrast, compared with the CNT group, both the depolarization-induced force (−51%) and the Ca²⁺-activated maximum specific force (−32%) were markedly reduced in skinned fibers from the SA group. These deleterious functional alterations were accompanied by decreases in the amount of DHPRα1, RYR, junctophilin 1, and SH3 and cysteine-rich domain 3 (STAC3) in SA muscles. Thus, these data clearly show that SA induces not only an increase in skeletal muscle fiber hypertrophy but also leads to a reduction in the intrinsic contractile dysfunction due to the excitation–contraction uncoupling and impaired force-generating capacity.