Muscle healing is a complex biological process that involves multiple stages of repair, including inflammation, proliferation, and remodeling. While this cycle is often sufficient, in cases of volumetric or extreme muscle loss (VML), the body’s natural repair mechanisms can fall short, leading to incomplete restoration of muscle function after injury, disease, or aging. Many existing treatments for muscle injury fail to adequately promote angiogenesis, leading to insufficient blood flow to the injury site. Fibrosis is another common complication that can prevent muscle regeneration and increase the risk of reinjury. Given that skeletal muscle comprises nearly half of the human body and muscle injuries are becoming increasingly prevalent, it is vital to develop new strategies to enhance muscle repair. Understanding these healing mechanisms is essential for creating therapeutic approaches that minimize scar formation and improve muscle functionality across a range of conditions, from sports injuries to age-related degenerative musculoskeletal diseases. This chapter will explore current biological methods to improve muscle healing, address gaps in existing approaches, and emphasize the role of cellular senescence. Finally, it will review emerging research, with a focus on the potential of estrogen-related receptors (ERRs) in enhancing muscle regeneration.