Mechanisms and role of PERM1 in skeletal muscle oxidative capacity and exercise-induced responses

Regular exercise can prevent or delay chronic metabolic diseases, such as diabetes, hypertension, and heart disease. The capacity for exercise relies on the health of skeletal muscle, as well as the muscle’s ability to respond and adapt to the energy demands of exercise, by increasing mitochondrial content and oxidative capacity. Skeletal muscle relies on two distinct subpopulations of mitochondria: those underneath the sarcolemma [subsarcolemmal mitochondria (SSM)] and those in between the myofibrils [intermyofibrillar mitochondria (IMFM)]. Together, these mitochondrial populations form a reticular network that is thought to facilitate energy distribution throughout the muscle fiber. The mechanisms that underlie the unique architecture and spatial distribution of mitochondria in striated muscle are largely unknown. Moreover, while we know of signaling pathways (e.g., Ca2+ signaling) and transcriptional regulators (e.g., PGC-1α) that are present in many cell types and drive mitochondrial biogenesis, we know little about tissue-specific regulators of mitochondrial biogenesis and function. Our lab has identified PGC-1/ERR Regulator in skeletal Muscle 1 (PERM1) as a cardiac-and skeletal muscle-specific regulator that enhances oxidative capacity and contributes to mitochondrial adaptations in response to training. Strikingly, Perm1 expression is absent in many other tissues with high mitochondrial content (e.g., liver or kidney), suggesting a role specific to striated muscle. While past studies have defined the impact of PERM1 on mitochondrial biogenesis and respiratory capacity, the molecular mechanism by which PERM1 exerts such effects is largely unknown. To gain insights into the underlying mechanism, we have generated mouse models overexpressing or lacking PERM1 and taken proteomic approaches to identify PERM1-interacting proteins. Our biochemical studies show PERM1 interacting with the outer mitochondrial membrane protein Samm50 and co-purifying with mitochondria, dependent on a C terminal domain of PERM1. We also find PERM1 associates with ankyrins (AnkR, AnkB and AnkG) via a N terminal domain, and Ca2+/calmodulin dependent kinases. Our mouse models show that overexpression or deletion of PERM1 increase or decrease, respectively, exercise fitness and alter substrate metabolism during exercise. Perm1 KO skeletal muscles have reduced mitochondrial content and a notable change in mitochondrial distribution, with a specific loss of SS mitochondria. My ongoing studies aim in defining the contribution of PERM1 to mitochondrial content, spatial organization, and function, as well as testing the hypothesis that PERM1 promotes activity-dependent Ca2+/calmodulin-dependent kinase II (CaMKII) signaling and changes in gene expression by acting as a scaffold protein that links mitochondria to other subcellular structures / signaling complexes. NIDDK This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.