Impaired overload-induced hypertrophy in obese Zucker rat slow-twitch skeletal muscle

Abstract

The effect of insulin resistance (IR) on the adaptation of skeletal muscle loading is not well understood. Here we examine whether the soleus muscles of the lean Zucker (LZ) and insulin-resistant obese Zucker (OZ) rat exhibit differences in their ability to undergo muscle hypertrophy following 8 wk of mechanical overload. Four-week-old male LZ (n = 5) and OZ (n = 5) rats underwent unilateral surgical ablation of the gastrocnemius muscle while the contralateral hindlimb was used as an internal control. Mechanical overload increased soleus muscle wet weight (LZ 57% and OZ 33%, respectively; P < 0.05) and average type 1 fiber cross-sectional area (LZ 32% and OZ 5%, respectively; P < 0.05) in LZ and OZ rats, while the magnitude of these increases was greater in the LZ animals (P < 0.05). The reduced degree of muscle hypertrophy observed in the OZ animals was associated with decreases in the ability of the OZ soleus muscle to phosphorylate p70s6k(Thr 389) and mTOR, while phosphorylation of p70s6k(Thr 389) was increased in the LZ overloaded soleus by 83% (P < 0.05). The amount of Tuberin/TSC2 phosphorylation, an inhibitor of mTOR, was unchanged in the LZ soleus after overload while it was increased (68.3%, P < 0.05) in OZ animals. Conversely, AMPK phosphorylation was decreased in the LZ (-22.77%, P < 0.05) but increased (57%, P < 0.05) in the OZ soleus with overload. Taken together, these data suggest that IR or other related comorbidities may impair the ability of the soleus to activate mTOR signaling and undergo load-induced muscle hypertrophy.

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat

“…2). This latter finding is consistent with our data demonstrating that the insulin-resistant soleus exhibits a reduced ability to undergo hypertrophy following 8 wk of mechanical overload (33). To examine how this defect in mTOR signaling might affect the regulation of molecules thought to be involved in controlling protein translation, we next examined how insulin resistance affected the phosphorylation of 4E-BP1 and p70S6k in response to increased muscle loading.…”

“…Previous work by our laboratory has demonstrated that the degree of soleus muscle hypertrophy following 8 wk of compensatory overload appears to be blunted in the insulin-resistant OZ rat compared with its lean counterpart (33). Here we examine the time course of muscle growth and the activation of mTOR and mTOR-related signaling at 1 and 3 wk of overload in an effort to better understand why muscle hypertrophy may be diminished in the OZ rat.…”

AICAR-induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C2C12skeletal muscle cells

“…It has been reported that activation of AMPK inhibits myogenesis (9,27,41) and hypertrophy of skeletal muscle cells (22,28,30) and rodent skeletal muscle (22,28). Negative correlation between AMPK activity and the degree of hypertrophy in rat muscle have also been reported (35,39). These responses appear to be related to the deactivation of the signals in the protein synthesis pathway, mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70 S6K ) (2,22,28), and to the activation of the signals in the protein degradation pathway, Forkhead box O transcription factors (Foxo) (31,36,41) and muscle-specific E3 ubiquitin ligases, such as muscle RING-finger 1 (MuRF1) and atrogin-1/muscle atrophy F-box (MAFbx) (19,30).…”

Differential regulation of apoptosis in slow and fast twitch muscles of aged female F344BN rats

“…The role that myofiber loss plays in age-related muscle atrophy is not fully understood; however, recent data has suggested that the elderly may experience significant losses in total fiber number (~30-40 % of total fibers) between the second and eighth decade of life [8]. More recently, other work has demonstrated that apoptosis may play a considerable role in mediating age-related muscle atrophy in both rats and humans [9][10][11].…”