Abstract
TGF-β1 is known to inhibit muscle regeneration after muscle injury. However, it is unknown if high systemic levels of TGF-β can affect the muscle regeneration process. In the present study, we demonstrated the effect of a CCl4 intra-peritoneal injection and losartan (an angiotensin II type 1 receptor antagonist) on skeletal muscle (gastrocnemius muscle) injury and regeneration. Male C57BL/6 mice were grouped randomly as follows: control (n = 7), CCl4-treatment group (n = 7), and CCl4 + losartan treatment group (n = 7). After CCl4 treatment for a 16-week period, the animals were sacrificed and analyzed. The expression of dystrophin significantly decreased in the muscle tissues of the control group, as compared with that of the CCl4 + losartan group (p < 0.01). p(phospho)-Smad2/3 expression significantly increased in the muscles of the control group compared to that in the CCl4 + losartan group (p < 0.01). The expressions of Pax7, MyoD, and myogenin increased in skeletal muscles of the CCl4 + losartan group compared to the corresponding levels in the control group (p < 0.01). We hypothesize that systemically elevated TGF-β1 as a result of CCl4-induced liver injury causes skeletal muscle injury, while losartan promotes muscle repair from injury via blockade of TGF-β1 signaling.
Highlights
Carbon tetrachloride (CCl4) is a toxic chemical that is often employed to study the mechanisms of hepatotoxic effects associated with hepatic steatosis, fibrosis, and hepatocellular carcinogenicity [1]
We show for the first time that skeletal muscle is impaired by the production of TGF-β1 as a result of CCl4-induced chronic liver injury, and that the blockade of angiotensin II type 1 receptor by losartan treatment is protective against TGF-β1-induced skeletal muscle injury
Chronic intraperitoneal administration of CCl4 induces liver injury, and in turn leads to skeletal muscle injury
Summary
Carbon tetrachloride (CCl4) is a toxic chemical that is often employed to study the mechanisms of hepatotoxic effects associated with hepatic steatosis, fibrosis, and hepatocellular carcinogenicity [1]. TGF-β and reactive oxygen species (ROS), which are released from the liver in high amounts after CCl4 treatment [1,5], seem to induce secondary damage to other organs such as skeletal and cardiac muscle. The treatment of patients with AT-II receptor blockade results in ameliorated muscle wasting and reduced amounts of adipose tissue in their skeletal muscle tissues [13]. We show for the first time that skeletal muscle is impaired by the production of TGF-β1 as a result of CCl4-induced chronic liver injury, and that the blockade of angiotensin II type 1 receptor by losartan treatment is protective against TGF-β1-induced skeletal muscle injury
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