Skeletal muscle specific Perm1 overexpression preserves maximal force following denervation injury
Authors: Gilmore Natalie , Cho Yoshitake , Ross Robert 
Published: May 2023

Perm1 (PPARGC1- and ESRR-induced regulator, muscle 1) is a mitochondrial (Mito) protein highly expressed in skeletal and cardiac muscle that is downregulated in diseases such as Amyotrophic Lateral Sclerosis (ALS) and heart failure. It has previously been shown to be induced by endurance exercise and regulate Mito oxidative function and biogenesis. The objective of the study is to determine whether increased Perm1 expression in skeletal muscle (Skm) is able to attenuate the effects of Skm atrophy following denervation. We hypothesize that overexpression of the Perm1 gene specifically in Skm myofibers will protect against metabolic and functional alterations caused by disuse, resulting in preserved muscle size and force following denervation. Upregulation of Perm1 was achieved using a Skm-specific Perm1 transgenic mouse model (TG). Unilateral sciatic nerve excision was performed on 8-week old male Perm1 Skm TG and C57BL/6J wild-type (WT) control (CTL) mice. Skms were evaluated 2 weeks post denervation. Morphology / cross-sectional area (CSA) was analyzed in gastrocnemius (Gastroc) and ex-vivo contractility was measured in extensor digitorum longus (EDL) muscles using a force-frequency protocol (0.5 ms pulses, 16 V, 1-150 Hz, 300 ms trains once every 100 sec) performed at the muscle’s optimal length (L0). Western blotting was used to analyze expression of Mito and contractile proteins. The CSA of Gastroc was not significantly different between Perm1 Skm TG and CTL, either at baseline or following denervation (Student’s t-test). EDL contractility showed that maximal force, normalized to CSA, was preserved in Perm1 Skm TG denervated muscles compared to the contralateral CTL (non-denervated) muscles. Differences in maximal isometric force between CTL and denervated muscle was significant in the WT Skm, but relatively preserved in TG mice. Analysis of the force-frequency curves, which follow a sigmoidal trend, showed a similar trend as that of the maximal force. The delta in isometric force, between CTL and denervated Skm, throughout the entire curve was reduced in the TG vs the wider change noted in WT. Western blots show a preservation of Ckmt2, oxphos complex proteins II and IV, and Akt in the TG denervated muscles. Additional blots are being performed to extend these preliminary findings and also to investigate changes in other relevant proteins. In conclusion, Skm overexpression of the Mito protein Perm1 yielded a modest protective effect on contractility following Skm denervation, yet, did not protect against the reduction of muscle fiber size (CSA) caused by denervation. Ongoing work will further determine the effects of Perm1 overexpression on contractile and Mito protein expression in this and other models which perturb Skm function. Funding Sources: Veterans Administration Merit Award I01 BX004897 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.