BackgroundAged skeletal muscle is characterized by an increased incidence of metabolic and functional disorders, which if allowed to proceed unchecked can lead to increased morbidity and mortality. The mechanism(s) underlying the development of these disorders in aging skeletal muscle are not well understood. Protein kinase B (Akt/PKB) is an important regulator of cellular metabolism and survival, but it is unclear if aged muscle exhibits alterations in Akt function. Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention.Principal FindingsCompared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308) was higher in soleus muscles of very aged rats (33-months). Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR) phosphorylation, along with decreased levels of insulin receptor beta (IR-β), phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and phosphorylation of phosphoinositide-dependent kinase-1 (PDK1) (Ser241). In vitro Akt kinase measurements and ex vivo muscle incubation experiments demonstrated age-related impairments of Akt kinase activity, which were associated with increases in Akt S-nitrosylation and inducible nitric oxide synthase (iNOS). Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin. These age-related disorders were attenuated by treating aged (27-month) animals with acetaminophen (30 mg/kg body weight/day) for 6-months.ConclusionsThese data demonstrate that Akt dysfunction and increased S-nitrosylation of Akt may contribute to age-associated disorders in skeletal muscle and that acetaminophen may be efficacious for the treatment of age-related muscle dysfunction.

These results suggest that acetaminophen may be useful for the treatment of age-associated hyperglycemia.

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.

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Excess cardiac iron levels are associated with cardiac damage and can result in increased morbidity and mortality. Here, we hypothesize that elevations in tissue iron can activate caspasedependent signaling, which leads to increased cardiac apoptosis and fibrosis, and that these alterations can be attenuated by iron chelation. Using an iron-overloaded gerbil model, we show that increased cardiac iron is associated with reduced activation of Akt (Ser473 and Thr308), diminished phosphorylation of the proapoptotic regulator Bad (Ser136), and an increased Bax/Bcl-2 ratio. These iron-overload-induced alterations in Akt/ Bad phosphorylation and Bax/Bcl-2 ratio were coupled with increased activation of the downstream caspase-9 (40/38-and 17-kDa fragments) and apoptosis executioner caspase-3 (19-and 17-kDa fragments), which were accompanied by evidence of elevated cytoskeletal ␣-fodrin cleavage (150-and 120-kDa fragments), discontinuity of myocardial membrane dystrophin immunoreactivity, increases in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells (nucleic DNA fragmentation), and cardiac fibrosis. We demonstrate that the administration of deferasirox, a tridentate iron chelator, is associated with diminished tissue iron deposition, attenuated activation of caspases, reduced ␣-fodrin cleavage, improved membrane integrity, decreased TUNEL reactivity, and attenuated cardiac fibrosis. These results suggest that the activation of caspase-dependent signaling may play a role in the development of iron-induced cardiac apoptosis and fibrosis, and deferasirox, via a reduction in cardiac tissue iron levels, may be useful for decreasing the extent of iron-induced cardiac damage.