Stephen E. Alway

Gene expression of the NR4A nuclear orphan receptor NOR‐1 is reduced in obesity and in human skeletal muscle during disuse. It has been well established that NOR‐1 is highly responsive to both aerobic and resistance exercise and NOR‐1 overexpression is coincident with a plethora of metabolic benefits. However, it is unclear whether loss of NOR‐1 contributes to inappropriate metabolic signaling in skeletal muscle that could lead to insulin resistance. The purpose of this study was to elucidate the impact of NOR‐1 deficiency on C2C12 metabolic signaling. Changes in gene expression after siRNA‐mediated NOR‐1 knockdown in C2C12 myotubes were determined by qPCR and bioinformatic analysis of RNA‐Seq data. Our RNA‐Seq data identified several metabolic targets regulated by NOR‐1 and implicates NOR‐1 as a modulator of mTORC1 signaling via Akt‐independent mechanisms. Furthermore, pathway analysis revealed NOR‐1 knockdown perturbs the insulin resistance and insulin sensitivity pathways. Taken together, these data suggest skeletal muscle NOR‐1 deficiency may contribute to altered metabolic signaling that is consistent with metabolic disease. We postulate that strategies that improve NOR‐1 may be important to offset the negative impact that inactivity, obesity, and type 2 diabetes have on mitochondria and muscle metabolism.

Musculoskeletal health is directly linked to independence and longevity, but disease and aging impairs muscle mass and health. Complete repair after a pathological or physiological muscle injury is critical for maintaining muscle function, yet muscle repair is compromised after disuse, or in conditions such as metabolic diseases, cancer, and aging. Regeneration of damaged tissue is critically dependent upon achieving the optimal function of satellite cells (muscle stem cells, MSCs). MSC remodeling in muscle repair is highly dependent upon its microenvironment, and metabolic health of MSCs, which is dependent on the functional capacity of their mitochondria. Muscle repair is energy demanding and mitochondria provide the primary source for energy production during regeneration. However, disease and aging induce mitochondrial dysfunction, which limits energy production during muscle regeneration. Nevertheless, the role of mitochondria in muscle repair likely extends beyond the production of ATP and mitochondria could provide potentially important regulatory signaling to MSCs during repair from injury. The scope of current research in muscle regeneration extends from molecules to exosomes, largely with the goal of understanding ways to improve MSC function. This review focuses on the role of mitochondria in skeletal muscle myogenesis/regeneration and repair. A therapeutic strategy for improving muscle mitochondrial number and health will be discussed as a means for enhancing muscle regeneration. Highlights: (a). Mitochondrial dysfunction limits muscle regeneration; (b). Muscle stem cell (MSC) function can be modulated by mitochondria; (c). Enhancing mitochondria in MSCs may provide a strategy for improving muscle regeneration after an injury.