Activating the MasR/Ang1‐7 Pathway Reduces Muscle Atrophy and Function Loss Following Denervation

Muscle atrophy is defined as a decrease in muscle mass that eventually leads to partial or complete muscle wasting. Muscle atrophy occurs in a variety of conditions including chronic diseases such as heart failure, limb immobilization and following a complete loss of muscle activity after spinal cord injury (SCI) and peripheral nerve injury. A consequence of muscle atrophy is large force decrease associated with muscle mass loss as well as contractile components. As a result of the force loss, atrophy decreases quality of life as the patient becomes unable to perform certain tasks as well as worsens the risk of accident while performing those tasks. Preventing the atrophy following peripheral nerve injury and thus muscle denervation will improve muscle physiology, especially, when a long time is necessary for nerve regeneration to be completed. Recent studies have provided evidence that activation of the MasR/Ang1‐7 signaling pathway reverses muscle atrophy induced by Ang II in chronic disease and immobilization. The objective of this study was to determine whether Ang 1‐7 also reduces the atrophy process and force loss following muscle denervation. Mouse extensor digitorum longus (EDL) and soleus were denervated by removing 3–4 mm of the sciatic nerve at the thigh level. Denervated mice were then divided into 4 groups: i) denervated; ii) denervated and treated with Ang 1‐7 (osmotic pump 100 ng/kg body weight/min); iii) denervated and treated with diminazene aceturate (DIZE, oral gavage 15 mg/day/kg body weight), a ACE2 activator, to locally increase Ang 1‐7 levels, and iv) denervated and receiving sucrose (oral gavage 1 mg/day/kg body weight). A 5 th group of mice was used as control group, i.e., normal innervated muscle. The results show that Ang 1‐7 partially prevented muscle mass loss while fully preventing a loss of normalized force to CSA up to 4 week denervation period. The maintenance of the normalized maximum force by Ang 1‐7 suggests that muscle integrity, i.e., t‐tubules, sarcoplasmic reticulum (SR), and sarcomere, and functionality, i.e., membrane excitability, Ca 2+ release and force, are better maintained. This study is thus providing evidence that Ang 1, 7 has therapeutic potential to prevent function loss following a denervation. Support or Funding Information This study was supported by the National Science and Engineering Research Council of Canada (NSERC) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .