Perm1 regulates CaMKII activation and shapes skeletal muscle responses to endurance exercise training

Yoshitake Cho, Shizuko Tachibana, Bethany C. Hazen, James J. Moresco, John R. Yates, Bernard Kok, Enrique Saez, Robert S. Ross, Aaron P. Russell, Anastasia Kralli

Skeletal muscle plays key roles in metabolic homeostasis and whole-body energy expenditure. Endurance exercise training remodels skeletal muscle by activating signaling pathways and regulating transcription factors. Perm1, a recently identified protein, is selectively expressed in skeletal and cardiac muscles. To gain insights into the cellular function of Perm1, Cho et al. searched for Perm1 interacting proteins. They show that Perm1 regulates physical activity-dependent CaMKII and MAPK p38 signaling and is important for a subset of exercise-induced responses. Their findings suggest that Perm1 modulates excitation-transcription coupling and shapes the response to endurance exercise.

Objective: Endurance exercise training remodels skeletal muscle, leading to increased mitochondrial content and oxidative capacity. How exercise entrains skeletal muscle signaling pathways to induce adaptive responses remains unclear. In past studies, we identified Perm1 (PGC-1 and ERR induced regulator, muscle 1) as an exercise-induced gene and showed that Perm1 overexpression elicits similar muscle adaptations as endurance exercise training. The mechanism of action and the role of Perm1 in exercise-induced responses are not known. In this study, we aimed to determine the pathway by which Perm1 acts as well as the importance of Perm1 for acute and long-term responses to exercise.

Methods: We performed immunoprecipitation and mass spectrometry to identify Perm1 associated proteins, and validated Perm1 interactions with the Ca2+/calmodulin-dependent protein kinase II (CaMKII). We also knocked down Perm1 expression in gastrocnemius muscles of mice via AAV-mediated delivery of shRNA and assessed the impact of reduced Perm1 expression on both acute molecular responses to a single treadmill exercise bout and long-term adaptive responses to four weeks of voluntary wheel running training. Finally, we asked whether Perm1 levels are modulated by diet or diseases affecting skeletal muscle function.

Results: We show that Perm1 associates with skeletal muscle CaMKII and promotes CaMKII activation. In response to an acute exercise bout, muscles with a knock down of Perm1 showed defects in the activation of CaMKII and p38 MAPK and blunted induction of regulators of oxidative metabolism. Following four weeks of voluntary training, Perm1 knockdown muscles had attenuated mitochondrial biogenesis. Finally, we found that Perm1 expression is reduced in diet-induced obese mice and in muscular dystrophy patients and mouse models.

Conclusions: Our findings identify Perm1 as a muscle-specific regulator of exercise-induced signaling and Perm1 levels as tuners of the skeletal muscle response to exercise. The decreased Perm1 levels in states of obesity or muscle disease suggest that Perm1 may link pathological states to inefficient exercise responses.