Pathophysiology of Sarcopenia
Core Pathophysiological Mechanisms
Sarcopenia results from an imbalance between anabolic and catabolic muscle homeostasis, driven by aging-related changes in neuromuscular function, altered protein turnover, hormonal decline, chronic inflammation, and oxidative stress. 1, 2
Primary Age-Related Changes
- Muscle mass decline begins at age 40 years with an 8% decrease per decade, accelerating to 15% per decade after age 70 years 3, 4
- Progressive denervation of muscle fibers occurs with aging, leading to loss of motor units and impaired neuromuscular transmission 5
- Age-related alterations in muscle protein synthesis and breakdown create a net catabolic state, with decreased efficiency of protein synthesis even when adequate amino acids are available 2
Inflammatory and Metabolic Dysregulation
- Chronic low-grade inflammatory activity (inflammaging) plays a central role, with elevated inflammatory markers driving muscle catabolism 6, 2
- Intracellular oxidative stress accumulates in aging muscle, damaging cellular components and impairing mitochondrial function 2, 5
- Enhanced myostatin signaling inhibits muscle growth and regeneration pathways 5
- Insulin resistance develops in aging muscle, reducing anabolic signaling and protein synthesis 1
Hormonal Alterations
- Aging causes decline in anabolic hormones including testosterone, growth hormone, and IGF-1, which are critical for muscle protein synthesis and regeneration 7, 2
- Alterations in hormonal networks affect inflammatory processes, muscle regeneration capacity, and protein synthesis efficiency 7
- Changes in endocrine function contribute to both the inflammatory milieu and reduced muscle repair capacity 7
Nutritional and Metabolic Factors
- Inadequate protein and energy intake, malabsorption, and micronutrient deficiencies (particularly B vitamins) directly impair muscle maintenance 3
- B vitamin deficiencies (thiamine, niacin, B6, folate, B12) impair neuromuscular function through reduced activity of vitamin-dependent enzymes in mitochondria, increased reactive oxygen species production, and inflammatory responses with microglial activation 3
- Vitamin B1 deficiency specifically triggers immune responses that cause irreversible neural tissue loss affecting muscle innervation within 9-11 days 3
Secondary Sarcopenia Mechanisms
- Physical inactivity and immobilization cause rapid muscle loss—seven days of bedrest results in 1 kg loss of lean leg muscle mass in older adults 4, 6
- Chronic diseases (diabetes, cardiovascular disease, chronic kidney disease, cancer) accelerate sarcopenia through disease-specific inflammatory pathways and metabolic derangements 3, 1
- Disease burden and acute illness create catabolic stress that overwhelms anabolic capacity 3
Sarcopenic Obesity Pathophysiology
- Obesity stimulates sarcopenia by altering lipid metabolism, promoting insulin resistance, activating inflammatory pathways, and causing fat deposition into skeletal muscle (myosteatosis) 3
- The combination creates worse functional outcomes than either condition alone through synergistic metabolic dysfunction 3
Tissue-Level Changes
- Reduction in both type I and type II muscle fiber size and number, with preferential loss of type II (fast-twitch) fibers 6, 2
- Increased intramuscular fat infiltration (myosteatosis) reduces muscle quality and contractile function 3
- Impaired muscle regeneration capacity due to satellite cell dysfunction and reduced proliferative potential 2
Multifactorial Integration
The pathophysiology represents a complex interaction where aging, disuse, chronic disease, inflammation, hormonal decline, nutritional inadequacy, and oxidative stress create a self-perpetuating cycle of muscle loss 6, 2. Each factor amplifies the others, making sarcopenia a progressive condition that requires addressing multiple mechanisms simultaneously for effective intervention 4, 8.