Skeletal muscle is a dynamic tissue regulated by pathways that control protein and cell turnover. During muscle atrophy, proteolytic systems are activated, leading to the removal of contractile proteins and organelles, resulting in muscle fiber shrinkage. Excessive muscle loss is associated with poor prognosis in diseases like myopathies, muscular dystrophies, cancer, diabetes, sepsis, and heart failure. Muscle atrophy also occurs with aging. This review discusses the key mechanisms regulating the turnover of contractile proteins and organelles in muscle, and how impairments in these mechanisms contribute to atrophy. It also explores how protein synthesis and degradation are regulated by signaling pathways influenced by mechanical stress, physical activity, and nutrient availability. The ubiquitin-proteasome system is crucial for removing sarcomeric proteins during muscle activity changes. Muscle atrophy is associated with increased ubiquitin conjugation, proteasomal activity, and upregulation of ubiquitin-related genes. Key ubiquitin ligases involved in muscle atrophy include atrogin-1 and MuRF1. These ligases regulate the half-life of proteins essential for muscle function, such as MyoD and IRS1. Genetic studies have shown that mice lacking these ligases are resistant to muscle atrophy. Other E3 ligases, such as TRAF6 and Trim32, also play roles in muscle atrophy by regulating protein degradation and autophagy. The autophagy-lysosome system is also critical for muscle homeostasis. Autophagy can be both catabolic and compensatory, playing a role in mitochondrial remodeling and the removal of damaged organelles. Genetic studies have shown that autophagy is essential for maintaining muscle mass and preventing atrophy. Mutations in autophagy-related genes can lead to muscle disorders, such as congenital muscular dystrophies. Autophagy is also involved in sarcopenia, the age-related loss of muscle mass. Signaling pathways such as IGF1-Akt-FoxO, myostatin, NFκB, and glucocorticoids regulate muscle atrophy. The IGF1-Akt-FoxO pathway is crucial for muscle growth and preventing atrophy. Akt inhibits FoxO, which in turn upregulates atrogin-1 and MuRF1. Myostatin, a TGFβ family member, acts as a negative regulator of muscle growth. However, it can also contribute to atrophy by activating FoxO and upregulating atrogin-1. NFκB signaling is involved in inflammation and muscle wasting, with TNFα and TWEAK playing roles in muscle atrophy. The crosstalk between these pathways is complex, with interactions between Akt, FoxO, IGF1, myostatin, and NFκB. Understanding these pathways provides new therapeutic targets for preventing and treating muscle atrophy in metabolic and neuromuscular diseases.Skeletal muscle is a dynamic tissue regulated by pathways that control protein and cell turnover. During muscle atrophy, proteolytic systems are activated, leading to the removal of contractile proteins and organelles, resulting in muscle fiber shrinkage. Excessive muscle loss is associated with poor prognosis in diseases like myopathies, muscular dystrophies, cancer, diabetes, sepsis, and heart failure. Muscle atrophy also occurs with aging. This review discusses the key mechanisms regulating the turnover of contractile proteins and organelles in muscle, and how impairments in these mechanisms contribute to atrophy. It also explores how protein synthesis and degradation are regulated by signaling pathways influenced by mechanical stress, physical activity, and nutrient availability. The ubiquitin-proteasome system is crucial for removing sarcomeric proteins during muscle activity changes. Muscle atrophy is associated with increased ubiquitin conjugation, proteasomal activity, and upregulation of ubiquitin-related genes. Key ubiquitin ligases involved in muscle atrophy include atrogin-1 and MuRF1. These ligases regulate the half-life of proteins essential for muscle function, such as MyoD and IRS1. Genetic studies have shown that mice lacking these ligases are resistant to muscle atrophy. Other E3 ligases, such as TRAF6 and Trim32, also play roles in muscle atrophy by regulating protein degradation and autophagy. The autophagy-lysosome system is also critical for muscle homeostasis. Autophagy can be both catabolic and compensatory, playing a role in mitochondrial remodeling and the removal of damaged organelles. Genetic studies have shown that autophagy is essential for maintaining muscle mass and preventing atrophy. Mutations in autophagy-related genes can lead to muscle disorders, such as congenital muscular dystrophies. Autophagy is also involved in sarcopenia, the age-related loss of muscle mass. Signaling pathways such as IGF1-Akt-FoxO, myostatin, NFκB, and glucocorticoids regulate muscle atrophy. The IGF1-Akt-FoxO pathway is crucial for muscle growth and preventing atrophy. Akt inhibits FoxO, which in turn upregulates atrogin-1 and MuRF1. Myostatin, a TGFβ family member, acts as a negative regulator of muscle growth. However, it can also contribute to atrophy by activating FoxO and upregulating atrogin-1. NFκB signaling is involved in inflammation and muscle wasting, with TNFα and TWEAK playing roles in muscle atrophy. The crosstalk between these pathways is complex, with interactions between Akt, FoxO, IGF1, myostatin, and NFκB. Understanding these pathways provides new therapeutic targets for preventing and treating muscle atrophy in metabolic and neuromuscular diseases.