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Atrophy

Atrophy is the decrease in size or wasting away of a cell, tissue, organ, or multiple organs, typically resulting from cellular shrinkage due to the loss of organelles, cytoplasm, and proteins, which can lead to cell death.^[1] This process is a common pathological response associated with various conditions, including disease, injury, malnutrition, or disuse, and it differs from necrosis by involving gradual degeneration rather than acute cell death.^[2] Atrophy can be classified into several types based on its underlying mechanisms. Physiologic atrophy occurs due to normal lack of use, such as the wasting of muscles during prolonged immobilization or bed rest, and is often reversible through exercise and improved nutrition.^[3] Pathologic atrophy arises from disease processes, including chronic inflammation, hormonal imbalances, or ischemia, leading to tissue loss, which may be partially reversible depending on the underlying cause.^[4] Neurogenic atrophy, another key type, results from damage to innervating nerves, causing denervation and subsequent muscle fiber shrinkage, as seen in conditions like spinal muscular atrophy.^[5] The causes of atrophy are diverse and interconnected, often involving imbalances in protein synthesis and degradation pathways, such as upregulation of ubiquitin-proteasome systems or autophagy.^[6] Common triggers include aging (sarcopenia), where muscle mass declines by about 1-2% annually after age 50; endocrine disorders like Cushing's syndrome, which promote catabolism; and neurodegenerative diseases, exemplified by brain atrophy in Alzheimer's, reducing gray matter volume by up to 20% in affected regions.^[7]^[8] In clinical contexts, atrophy contributes to functional impairments, such as weakness, reduced mobility, and organ failure, underscoring its role as a hallmark of progressive disorders.^[9]

Overview and Definition

Definition

Atrophy derives from the Greek term atrophia, meaning "a wasting away" or "lack of nourishment," a concept that entered English medical terminology in the 17th century.^[10] In biology, atrophy refers to the partial or complete wasting away of a body part, characterized by a progressive decline in the size of cells, tissues, or organs due to the loss of cell substance.^[11] This process primarily manifests as a reduction in cell size, distinguishing it from cell death mechanisms such as apoptosis, which decreases cell number through programmed elimination, or necrosis, involving uncontrolled tissue damage.^[1] Unlike these, atrophy often involves shrinkage of existing cellular components, including organelles and cytoplasm, without immediate loss of viable cells.^[12] A key feature of atrophy is its potential reversibility in certain cases, particularly when the inciting stimulus—such as disuse—is removed, allowing cells to regain size through restored metabolic activity and protein synthesis.^[13] The term's early recognition in medical literature dates to the 17th century, when anatomists like Elias Tillandz described tissue shrinkage observed in postmortem examinations as a form of bodily decline.^[14] Atrophy encompasses both physiological adaptations, such as those in normal development, and pathological states linked to disease, though these distinctions are explored further elsewhere.^[11]

Physiological vs. Pathological Atrophy

Physiological atrophy refers to the adaptive reduction in tissue size and function that occurs as part of normal developmental processes or environmental adaptations, without causing harm or impairment.^[15] This form of atrophy is typically programmed and reversible or self-limiting, allowing the body to reallocate resources efficiently. For instance, the involution of the thymus gland exemplifies physiological atrophy; the thymus reaches its peak size during adolescence but undergoes gradual shrinkage due to hormonal influences, particularly sex steroids, significantly reducing its functional mass by early adulthood as the immune system matures and shifts reliance to peripheral T-cell maintenance.^[16] Other examples include post-lactational mammary gland atrophy, where secretory lobules regress through programmed cell death after weaning, restoring the gland to a pre-pregnancy state, and the reduction in uterine size post-menopause, driven by estrogen decline, which significantly decreases the organ's mass while maintaining basic structural integrity.^[17]^[18] Similarly, bone remodeling in response to disuse in healthy individuals, such as during short-term reduced loading, represents an adaptive physiological process that adjusts bone density without leading to fragility.^[19] In contrast, pathological atrophy arises from disease, injury, chronic stress, or malnutrition, resulting in excessive tissue loss that impairs function and may progress if untreated.^[15] A classic example is disuse atrophy following immobilization, such as in a cast or bed rest due to injury, where muscle mass can decrease by approximately 0.5-1% per day initially, accompanied by inflammation and proteolysis, leading to weakness and delayed recovery.^[20] This differs from physiological disuse by involving disrupted signaling pathways, such as elevated ubiquitin-proteasome activity, and potential secondary complications like fibrosis.^[21] The key distinctions between physiological and pathological atrophy lie in their etiology, reversibility, and impact: physiological atrophy is hormonally or developmentally regulated, non-inflammatory, and beneficial for adaptation, whereas pathological atrophy often features inflammatory mediators, nutritional deficits, or toxic insults, rendering it progressive and detrimental to health.^[1] Aging-related atrophy, such as sarcopenia, occupies a borderline position; it involves gradual muscle loss starting around age 30 at 1-2% per year, accelerating after 60 to 3-5% annually due to hormonal shifts and reduced activity, but is considered physiological unless exacerbated by comorbidities into a pathological state.^[22]^[23]^[24]

Causes and Mechanisms

General Causes

Atrophy can arise from a variety of external and internal factors that disrupt the balance between tissue synthesis and degradation, leading to a reduction in cell size and organ volume across multiple tissue types.^[1] External influences often involve physical or environmental stressors, while internal factors stem from systemic physiological changes. These causes are broadly applicable and can overlap, contributing to both physiological and pathological forms of atrophy.^[3] Denervation, the loss of nerve supply to tissues, is a primary external cause of atrophy, commonly occurring after events such as spinal cord injury or peripheral nerve trauma. This leads to rapid muscle wasting, with significant mass loss observable within weeks due to the interruption of neurotrophic signals essential for tissue maintenance.^[25]^[26] Prolonged disuse or immobility represents another key external trigger, as seen in conditions like extended bed rest or limb immobilization from casting. Such inactivity results in swift tissue degradation, with initial muscle mass loss of approximately 0.5% per day in the early phases, driven by reduced mechanical loading and subsequent downregulation of anabolic pathways.^[27]^[28] Malnutrition, particularly protein-calorie deficiency as in starvation or severe undernourishment, induces atrophy by depriving tissues of essential substrates needed for protein synthesis and cellular upkeep. This systemic external factor causes widespread organ size reduction, including shrinkage of the liver, heart, and gastrointestinal tract, through impaired nutrient assimilation and increased catabolic demands.^[29]^[30] Ischemia, characterized by diminished blood flow, starves tissues of oxygen and nutrients, promoting atrophy in affected areas. For instance, in peripheral artery disease, chronic vascular occlusion leads to progressive tissue wasting, particularly in skeletal muscle, as hypoxic conditions favor degradative processes over repair.^[31]^[32] Among internal causes, hormonal imbalances such as excess glucocorticoids in Cushing's syndrome accelerate protein breakdown and inhibit synthesis, resulting in notable muscle and connective tissue atrophy. Patients with this condition often exhibit proximal muscle weakness due to glucocorticoid-mediated catabolism.^[33] Aging contributes intrinsically through cellular senescence, where accumulated senescent cells impair regenerative capacity and promote low-grade inflammation, leading to baseline atrophy rates across organs like muscle and brain. This process underlies sarcopenia and other age-related tissue declines, with senescent cell burden increasing progressively from midlife onward.^[34]^[35] Iatrogenic causes, often linked to medical interventions, include the side effects of long-term corticosteroid therapy, which mimics endogenous glucocorticoid excess and induces myopathy with muscle fiber atrophy. Chronic use of these drugs, prescribed for inflammatory conditions, can lead to significant tissue loss, particularly in type II muscle fibers, reversible upon dose reduction in many cases.^[36]^[33]

Cellular and Molecular Mechanisms

Atrophy at the cellular level involves a coordinated activation of catabolic processes that lead to the net loss of cellular components, primarily through enhanced protein degradation and reduced biosynthesis. These mechanisms are triggered by various stressors, such as nutrient deprivation or hormonal imbalances, resulting in the breakdown of structural proteins and organelles to recycle amino acids and maintain cellular homeostasis. The ubiquitin-proteasome system (UPS) serves as the primary pathway for selective protein degradation during atrophy, accounting for the majority of intracellular protein turnover. In this system, target proteins are tagged with polyubiquitin chains by a cascade involving E1 activating enzymes, E2 conjugating enzymes, and E3 ubiquitin ligases, marking them for degradation by the 26S proteasome. Muscle-specific E3 ligases, such as MAFbx (also known as atrogin-1) and MuRF1, are upregulated in atrophic conditions and specifically target contractile proteins like myosin heavy chain and actin for ubiquitination. The ubiquitination process can be represented as:

\text{Protein substrate} + n \cdot \text{Ubiquitin} \xrightarrow{\text{E1-E2-E3 ligase complex}} \text{Polyubiquitinated protein} \to \text{26S proteasome degradation}

This pathway is essential for rapid protein breakdown, with MAFbx/atrogin-1 promoting the degradation of regulatory factors and MuRF1 focusing on myofibrillar components. Complementing the UPS, the autophagy-lysosomal pathway facilitates the bulk degradation of cytoplasmic contents, including damaged organelles and protein aggregates, which becomes prominent under conditions of energy stress. Macroautophagy, the dominant form in atrophy, involves the formation of autophagosomes that engulf cellular material and fuse with lysosomes for hydrolytic breakdown, providing amino acids for energy production. This pathway is negatively regulated by the mechanistic target of rapamycin (mTOR) complex 1; inhibition of mTOR during nutrient deprivation, such as fasting, activates autophagy by dephosphorylating and activating transcription factors like TFEB and ULK1, leading to increased autophagosome formation. In atrophic cells, enhanced autophagy contributes to the loss of myofibrils and mitochondria, exacerbating tissue wasting.^[37] Transcriptional regulation plays a central role in coordinating these degradative pathways, with forkhead box O (FOXO) transcription factors acting as key mediators of atrophy gene expression. Under stress signals like insulin-like growth factor-1 (IGF-1) deficiency, FOXO proteins translocate to the nucleus following dephosphorylation by reduced Akt signaling, where they upregulate "atrogenes" such as MAFbx/atrogin-1 and LC3 for UPS and autophagy activation, respectively. This FOXO-dependent transcription promotes a pro-atrophic program that suppresses protein synthesis while enhancing breakdown, ensuring a sustained catabolic state.^[38] Mitochondrial dysfunction further drives atrophy by impairing energy production and promoting oxidative damage, creating a feedback loop of cellular shrinkage. Reduced mitochondrial biogenesis, mediated by downregulated PGC-1α, leads to fewer functional mitochondria, while increased reactive oxygen species (ROS) production from dysfunctional electron transport chains damages lipids, proteins, and DNA, triggering apoptosis-like processes and organelle fragmentation. This energy deficit activates AMPK, which inhibits mTOR and amplifies autophagy, contributing to the loss of cellular mass without full apoptosis.^[39] Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, inhibits muscle growth and is elevated in atrophic states, reinforcing catabolic signaling. Binding to activin type II receptors, myostatin activates Smad2/3 transcription factors, which suppress myogenic differentiation and promote FOXO activity, leading to enhanced UPS and autophagy. This pathway is particularly active in chronic atrophy, where sustained myostatin signaling limits hypertrophy and sustains wasting.^[21]^[40] The temporal dynamics of these mechanisms distinguish acute from chronic atrophy: acute phases, occurring over hours to days, primarily rely on rapid UPS activation for initial protein loss, whereas chronic atrophy involves sustained engagement of multiple pathways, including autophagy, transcriptional changes, mitochondrial impairment, and myostatin signaling, leading to progressive tissue decline.

Types of Atrophy by Tissue

Muscle Atrophy

Muscle atrophy refers to the progressive loss of muscle mass and strength, primarily affecting skeletal and cardiac muscles through distinct mechanisms and clinical contexts. In skeletal muscle, disuse atrophy arises from prolonged inactivity, such as immobilization following injury or bed rest, leading to rapid reductions in muscle size and function that can be largely reversed through targeted exercise interventions.^[41] Cachexia, in contrast, represents a systemic form of muscle wasting often associated with chronic conditions like cancer, characterized by involuntary weight loss greater than 5% of body weight over 6-12 months (or greater than 2% if BMI <20 kg/m²), often substantial in advanced stages, accompanied by inflammation and metabolic dysregulation that resists simple reversal.^[42] These types highlight the spectrum of muscle atrophy, from localized disuse effects to widespread catabolic states impacting overall physiology. In skeletal muscle, atrophy preferentially targets type II (fast-twitch) fibers, resulting in disproportionate loss of power-generating capacity and impaired explosive movements, while type I (slow-twitch) fibers are relatively spared.^[43] This selective vulnerability is compounded by dysfunction in satellite cells, the resident stem cells essential for muscle repair and regeneration, which exhibit reduced proliferation and differentiation during atrophic conditions, further hindering recovery.^[44] Cardiac muscle atrophy, often induced by mechanical unloading after heart transplantation or left ventricular assist device implantation, manifests as a substantial decline in ventricular mass—typically 20-25% within weeks—potentially compromising contractile efficiency despite aiding heart failure recovery.^[45] These tissue-specific changes underscore the unique physiological burdens, including diminished motility in skeletal muscle and altered hemodynamics in cardiac tissue. Muscle atrophy is commonly assessed through declines in cross-sectional area measured via magnetic resonance imaging (MRI) or muscle biopsy, which provide direct quantification of fiber size reduction, while functional markers like grip strength evaluate clinical impact on daily activities.^[46] Reversal is feasible, particularly for disuse atrophy, where exercise stimulates hypertrophy by reactivating the PI3K/Akt signaling pathway to enhance protein synthesis and inhibit degradation processes such as the ubiquitin-proteasome system (UPS) and autophagy.^[47] Prevalence is notably high among hospitalized elderly patients, affecting 30-50% and exacerbating risks of prolonged recovery and dependency.^[48]

Glandular Atrophy

Glandular atrophy refers to the progressive degeneration and reduction in size of endocrine and exocrine glands, leading to diminished secretory function and disruption of hormonal or enzymatic output. This process often involves impaired cellular maintenance due to chronic understimulation, autoimmune attack, or other stressors, resulting in feedback loop dysregulation that exacerbates the atrophy. In endocrine glands, such as those producing hormones for systemic regulation, atrophy can precipitate widespread homeostatic imbalances; in exocrine glands, it primarily affects localized secretion, like digestive enzymes or saliva. A prominent example in endocrine glands is adrenal atrophy caused by prolonged suppression of adrenocorticotropic hormone (ACTH), commonly seen after chronic exogenous glucocorticoid therapy. This suppression inhibits pituitary ACTH release via negative feedback, leading to reduced stimulation of the adrenal cortex and subsequent cortical thinning and functional loss. Abrupt withdrawal of steroids in such cases risks an Addisonian crisis, characterized by acute adrenal insufficiency with hypotension, hyponatremia, and hyperkalemia due to inadequate cortisol production.^[49]^[50]^[51] Thyroid gland atrophy exemplifies autoimmune-mediated glandular decline, particularly in Hashimoto's thyroiditis, where lymphocytic infiltration and antithyroid antibodies destroy follicular cells. Initial goiter formation from compensatory hyperplasia gives way to progressive shrinkage as parenchymal destruction advances, culminating in hypothyroidism with elevated thyroid-stimulating hormone (TSH) levels and reduced thyroxine output. This autoimmune process targets thyroid peroxidase and thyroglobulin, impairing hormone synthesis and leading to metabolic slowdown.^[52]^[53]^[54] In the exocrine domain, salivary gland atrophy in Sjögren's syndrome illustrates lymphocytic infiltration targeting acinar and ductal cells, severely curtailing saliva production—often reduced by more than 50% in unstimulated flow rates. This autoimmune exocrinopathy fosters dryness (xerostomia) and increases risks of oral infections and dental caries due to diminished antimicrobial and lubricating secretions. Similarly, pancreatic atrophy in type 1 diabetes involves autoimmune destruction of beta cells within the islets of Langerhans, leading to near-complete loss of insulin-producing beta cells and substantial pancreatic volume reduction (20-50%), which drives hyperglycemia and requires lifelong exogenous insulin therapy.^[55]^[56] Parathyroid atrophy, often secondary to chronic hypercalcemia from various etiologies, disrupts calcium homeostasis by diminishing parathyroid hormone (PTH) secretion, leading to hypocalcemia, hyperphosphatemia, and associated electrolyte imbalances such as neuromuscular irritability and tetany. Histologically, glandular atrophy across these examples features vacuolization of epithelial cells, loss of secretory granules, acinar shrinkage, and interstitial fibrosis, which collectively impair glandular architecture and regenerative capacity. These changes underscore the vulnerability of glandular tissues to sustained insults, amplifying systemic consequences through altered feedback mechanisms.^[57]^[58]^[59]^[60]

Reproductive System Atrophy

Reproductive system atrophy encompasses degenerative changes in the female and male reproductive organs, primarily driven by hormonal declines associated with aging, menopause, or therapeutic interventions. In females, estrogen deficiency following menopause leads to the genitourinary syndrome of menopause (GSM), formerly known as vaginal atrophy, characterized by thinning and inflammation of the vaginal epithelium, reduced vaginal lubrication, and an increase in vaginal pH from approximately 4.5 to between 5 and 7 due to loss of lactobacilli.^[61]^[62] This condition affects roughly 50% of postmenopausal women, resulting from diminished estrogen levels that impair epithelial cell maturation and collagen support in the vaginal walls.^[63] Uterine and ovarian atrophy also occur post-menopause, with the uterus shrinking to an average size of about 4.5 cm × 1.5 cm × 2.5 cm from its pre-menopausal dimensions, representing a reduction of approximately 50% in volume due to myometrial and endometrial thinning.^[64] The endometrium typically thins to less than 5 mm in unstimulated postmenopausal states, reflecting hypoestrogenic effects on glandular and stromal tissues.^[65] Ovarian atrophy involves progressive follicle depletion and stromal fibrosis, leading to a marked reduction in ovarian size and cessation of hormone production, which accelerates after age 40.^[66]^[67] In males, testicular atrophy arises from hypogonadism, where reduced testosterone and gonadotropin levels cause shrinkage of the seminiferous tubules, decreasing their diameter and impairing spermatogenesis, often resulting in diminished sperm production and fertility.^[68]^[69] Prostate atrophy is evident in aging or during androgen deprivation therapy (ADT) for prostate cancer, with glandular epithelium involution leading to a volume loss of 30-50% over months of treatment, as epithelial cells undergo apoptosis and stromal remodeling.^[70]^[71] Common symptoms of reproductive system atrophy include dyspareunia and urinary incontinence in females due to urogenital tissue fragility, while males may experience erectile dysfunction from vascular and hormonal deficits.^[72]^[73] Prevalence rises with advancing age, affecting over 40% of women beyond menopause and increasing in men over 60 due to natural androgen decline, with processes accelerated by chemotherapy, which induces premature ovarian or testicular follicle loss and hormonal suppression.^[74]^[75]

Nervous System Atrophy

Nervous system atrophy encompasses the progressive loss of neuronal tissue in both the central and peripheral components, leading to structural and functional deficits. In the brain, global atrophy occurs as a natural part of aging, with an annual volume loss of approximately 0.2% after age 35, accelerating to 0.5% by age 60, primarily affecting gray and white matter volumes.^[76] This process is exacerbated in pathological conditions, where regional atrophy predominates; for instance, in Alzheimer's disease, the hippocampus exhibits significant shrinkage, with annualized volume loss rates of about 4.66%, culminating in 20-30% reduction over five years.^[77] Such changes reflect the vulnerability of post-mitotic neurons, which lack the ability to divide and regenerate, making them particularly susceptible to accumulated damage from oxidative stress and metabolic demands.^[78] White matter atrophy involves the degeneration of myelinated tracts, often driven by demyelination processes that reduce overall tract volume and disrupt neural connectivity. In multiple sclerosis, for example, the loss of myelin sheaths—comprising 25-30% of white matter volume—directly contributes to brain parenchymal shrinkage, with secondary axonal loss in normal-appearing white matter further accelerating atrophy.^[79] This is distinct from global cortical thinning, as it primarily impairs signal transmission efficiency across brain regions. Peripheral nerve atrophy, conversely, arises from axonal degeneration following injury, initiating Wallerian degeneration where distal axons fragment and are cleared by Schwann cells, which undergo morphological changes to support debris removal but may themselves exhibit atrophic responses in chronic states.^[80]^[81] Measurement of nervous system atrophy relies heavily on neuroimaging techniques, particularly magnetic resonance imaging (MRI) volumetry, which quantifies tissue loss through segmentation of brain structures. Ventricular enlargement serves as a reliable proxy for cortical atrophy, as expanding cerebrospinal fluid spaces compensate for lost parenchymal volume, with studies showing correlations between lateral ventricle growth and overall brain shrinkage in aging and disease.^[82] Functionally, these atrophic changes manifest as cognitive decline, including memory impairment linked to hippocampal loss, and motor incoordination such as ataxia from cerebellar or white matter tract involvement, underscoring the irreversible nature of neuronal attrition in post-mitotic cells.^[83] Recent neuroimaging studies post-2023, including a 2025 analysis of UK Biobank data, have shown that the COVID-19 pandemic accelerated brain aging and volume loss, with effects observed even in uninfected individuals.^[84]

Atrophy in Diseases

Muscular Dystrophies and Myopathies

Muscular dystrophies and myopathies represent key categories of primary muscle disorders characterized by progressive atrophy due to genetic mutations or autoimmune processes. In muscular dystrophies, inherited defects lead to structural weaknesses in muscle fibers, resulting in ongoing degeneration and replacement of muscle tissue with fat and fibrosis. Myopathies, particularly inflammatory variants, involve immune-mediated damage that exacerbates muscle wasting through chronic inflammation and weakness. These conditions primarily affect skeletal muscles, leading to significant functional impairment, and are distinct from secondary atrophy caused by disuse or denervation. Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy, caused by X-linked recessive mutations in the DMD gene that result in absent or severely deficient dystrophin protein.^[85] Dystrophin normally stabilizes the muscle cell membrane during contraction; its absence causes membrane fragility, leading to repeated injury, necrosis, and eventual replacement of muscle fibers by fat and fibrotic tissue as the disease progresses.^[85] By adolescence, affected individuals often experience substantial muscle loss, with wheelchair dependence typically occurring around age 12 and significant cardiopulmonary complications by the late teens or early twenties.^[85] The condition predominantly affects males, with an incidence of approximately 1 in 5,000 newborn boys.^[86] Becker muscular dystrophy (BMD) arises from in-frame mutations in the same DMD gene, producing a partially functional, truncated dystrophin protein that allows for milder symptoms and slower disease progression compared to DMD.^[87] Initial proximal muscle weakness emerges in adolescence or early adulthood, with ambulation often preserved into the fourth or fifth decade, though cardiac involvement can occur independently of skeletal muscle severity.^[87] Like DMD, BMD leads to gradual muscle fiber degeneration and fibrofatty replacement, but the residual dystrophin mitigates the extent of membrane instability and early atrophy.^[88] Inflammatory myopathies, including polymyositis and dermatomyositis, contribute to muscle atrophy through autoimmune mechanisms targeting muscle tissue. Polymyositis is characterized by T-cell-mediated inflammation invading muscle fibers, causing direct cytotoxicity and progressive proximal weakness.^[89] Dermatomyositis shares similar muscle involvement but additionally features humoral immunity with perimysial inflammation and a distinctive cutaneous rash, such as heliotrope eyelids or Gottron's papules.^[89] Both conditions result in substantial muscle strength loss, alongside elevated serum creatine kinase and histopathological evidence of inflammatory infiltrates and fiber atrophy.^[90] Limb-girdle muscular dystrophies (LGMDs) form a heterogeneous group of autosomal disorders primarily affecting proximal muscles of the shoulders and hips, leading to symmetric weakness and atrophy.^[91] Traditionally classified into dominant (LGMD1) and recessive (LGMD2) types, they encompass over 30 subtypes with variable onset from childhood to adulthood and progression rates.^[92] Common features include waddling gait, scapular winging, and selective involvement of quadriceps or posterior thigh muscles, culminating in fibrofatty replacement similar to other dystrophies.^[91] The pathophysiology of these disorders centers on muscle membrane instability and chronic inflammation, which drive the atrophic process. In dystrophies like DMD and BMD, dystrophin deficiency disrupts the dystrophin-glycoprotein complex, rendering the sarcolemma susceptible to mechanical stress and calcium influx, which activates proteases and triggers necrosis.^[93] This cycle promotes chronic inflammation via immune cell recruitment, cytokine release, and fibrosis, exacerbating muscle loss.^[94] Inflammatory myopathies amplify this through adaptive immune responses, with T-cells in polymyositis directly lysing myofibers and autoantibodies in dermatomyositis complement-mediated damage.^[89] In LGMDs, defects in associated proteins like sarcoglycans further destabilize the membrane, fostering similar inflammatory and degenerative cascades.^[95] Genetically, muscular dystrophies arise from mutations in over 50 genes encoding components of the muscle cytoskeleton, extracellular matrix, or signaling pathways, with specific subtypes linked to distinct loci.^[96] For instance, LGMD subtypes 2C-2F (sarcoglycanopathies) result from recessive mutations in the SGCA, SGCB, SGCG, or SGCD genes, impairing the sarcoglycan subcomplex and leading to secondary dystrophin instability.^[95] These mutations often involve frameshifts, nonsense, or missense changes that abolish protein function, underscoring the genetic heterogeneity underlying progressive atrophy in these conditions.^[96]

Neurodegenerative Conditions

Neurodegenerative conditions are characterized by progressive neuron loss, which leads to atrophy in the nervous system and secondary muscle wasting due to denervation. In these diseases, atrophy manifests as shrinkage of brain regions or spinal cord structures, often resulting from the accumulation of misfolded proteins, oxidative stress, and excitotoxicity that trigger neuronal apoptosis. This neuronal degeneration disrupts neural circuits, causing downstream effects like muscle atrophy from loss of innervation, distinguishing it from primary muscle disorders. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, exemplifies motor neuron atrophy where upper motor neurons in the motor cortex and lower motor neurons in the spinal cord degenerate, leading to denervation atrophy in skeletal muscles. This process causes progressive muscle weakness and wasting, starting in the limbs or bulbar region. ALS affects approximately 2-5 individuals per 100,000 worldwide, with about 10% of cases being familial, often linked to mutations in the SOD1 gene that impair antioxidant defenses and promote protein aggregation. In Parkinson's disease, atrophy primarily affects the substantia nigra pars compacta, where up to 50% of dopaminergic neurons are lost by the time motor symptoms emerge, resulting in shrinkage of the basal ganglia and reduced dopamine signaling. This neuronal loss leads to bradykinesia, rigidity, and tremors, with atrophy extending to other areas like the locus coeruleus over time. The degeneration is driven by alpha-synuclein aggregates in Lewy bodies, which impair mitochondrial function and promote inflammation. Alzheimer's disease involves widespread cortical and hippocampal atrophy due to extracellular amyloid-beta plaques and intracellular tau tangles, which disrupt synaptic function and cause neuronal death. Hippocampal volume loss correlates with memory impairment, while cortical thinning affects executive functions, with atrophy progressing over years to involve multiple lobes. These pathological hallmarks lead to a loss of up to 30-50% of neurons in affected regions by advanced stages. In ALS, muscle atrophy typically begins distally in the hands or feet, spreading proximally to the trunk and proximal limbs over 2-5 years, reflecting the dying-back of motor axons from lower motor neuron degeneration. This pattern results in fasciculations, cramps, and eventual flaccid paralysis as denervated fibers undergo atrophy. Secondary muscle atrophy in neurodegenerative conditions arises from upper and lower motor neuron loss, leading to denervation without intrinsic muscle pathology, unlike primary myopathies such as muscular dystrophies where muscle fibers degenerate independently of neural input. This distinction underscores the need for therapies targeting neuronal survival to mitigate atrophy.

Other Disease-Associated Atrophy

Cancer cachexia is a multifactorial syndrome characterized by progressive loss of skeletal muscle mass, with or without fat mass loss, affecting 50-80% of patients with advanced cancer.^[97] This condition is driven by inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which promote muscle proteolysis and adipose tissue lipolysis, leading to severe wasting that contributes to approximately 20% of cancer-related deaths.^[98]^[99] In liver cirrhosis, atrophy manifests as progressive loss of hepatocytes accompanied by extensive fibrosis, resulting in a distorted architecture with the formation of regenerative nodules.^[100] This fibrotic replacement and nodular regeneration lead to a significant reduction in functional liver mass, impairing hepatic synthetic and metabolic functions.^[101] Bone atrophy, commonly presenting as osteopenia, arises in conditions such as prolonged disuse or primary hyperparathyroidism, where elevated parathyroid hormone levels accelerate bone resorption.^[102] Disuse leads to preferential loss of trabecular bone due to reduced mechanical loading, while hyperparathyroidism causes cortical and trabecular thinning through increased osteoclast activity.^[103] Diagnosis typically involves dual-energy X-ray absorptiometry (DEXA) scanning, where a T-score between -1.0 and -2.5 indicates osteopenia, signaling heightened fracture risk.^[104] Skin atrophy involves dermal thinning and loss of elasticity, often induced by chronic topical or systemic corticosteroid use or as part of intrinsic aging processes.^[105] Corticosteroids inhibit fibroblast activity and collagen synthesis, leading to reduced dermal collagen content, resulting in fragile, translucent skin prone to bruising and tearing.^[106] In aging, estrogen decline similarly diminishes collagen production, exacerbating epidermal and dermal atrophy.^[107] Renal atrophy in chronic kidney disease (CKD) is marked by tubular epithelial cell shrinkage and interstitial fibrosis, progressively reducing nephron function and overall kidney volume.^[108] This correlates with declining glomerular filtration rates and contributing to end-stage renal disease.^[109] HIV-associated lipodystrophy features selective subcutaneous fat atrophy, particularly in the face, limbs, and buttocks, often linked to antiretroviral therapy regimens like those containing stavudine or zidovudine.^[110] This peripheral lipoatrophy results in prominent facial hollowing and limb thinning, contrasting with possible central fat accumulation, and affects quality of life through visible cosmetic changes.^[111]

Diagnosis and Management

Diagnostic Methods

Diagnostic methods for atrophy encompass a range of clinical, imaging, electrophysiological, histological, biochemical, and functional assessments tailored to detect and quantify tissue volume loss across various systems, such as muscle, glandular, reproductive, and nervous tissues.^[112] These techniques enable early identification of atrophy by measuring structural changes, electrical activity, cellular morphology, molecular markers, and functional impairments, often integrated for comprehensive evaluation.^[113] Imaging modalities play a central role in visualizing and quantifying atrophy. Magnetic resonance imaging (MRI), particularly T1-weighted volumetric scans, is widely used to assess brain and muscle volume reductions, with voxel-based morphometry (VBM) enabling automated detection of gray matter atrophy as small as 1-5% through statistical voxel-wise comparisons.^[112]^[114] In glandular atrophy, computed tomography (CT) scans effectively measure size decreases, such as in submandibular glands affected by chronic sialolithiasis, where progressive volume loss is quantified via serial imaging.^[115] Electrophysiological testing, including electromyography (EMG), identifies denervation patterns indicative of muscle and nerve atrophy. Needle EMG detects spontaneous activity like fibrillation potentials and positive sharp waves in denervated fibers, which emerge within days to weeks post-injury and signal acute phases of atrophy.^[116]^[117] Muscle biopsy provides histological confirmation of atrophy through microscopic examination of tissue samples. In atrophied muscle, fibers often show reduced diameters below 50 μm compared to normal ranges of 40-80 μm in adults, with angulated or rounded morphologies distinguishing neurogenic from myopathic patterns.^[118]^[119]^[120] Biomarkers in serum offer non-invasive insights into atrophy processes. Elevated serum creatine kinase (CK) levels serve as an indicator for certain myopathies, such as inflammatory types, associated with muscle atrophy, correlating with disease severity and muscle damage.^[121]^[122] For neural atrophy, brain-derived neurotrophic factor (BDNF) levels in serum may reflect neurotrophic support deficits, though their role as a reliable biomarker requires further validation in aging and neurodegenerative contexts.^[123]^[124] Functional tests assess the clinical impact of atrophy on performance. The 6-minute walk test (6MWT) evaluates muscle endurance and mobility in conditions like spinal muscular atrophy, measuring distance covered to quantify functional decline.^[125]^[126] For cognitive aspects of nervous system atrophy, the Mini-Mental State Examination (MMSE) screens for impairments tied to brain volume loss, providing a standardized score for tracking progression.^[127] A recent advancement as of 2025 involves AI-enhanced MRI analysis for predicting early atrophy in aging populations. Machine learning models applied to single MRI scans estimate accelerated brain aging and dementia risk by quantifying subtle volume changes, offering higher sensitivity than traditional methods for non-invasive early detection. Additional 2025 developments include AI models achieving up to 95% accuracy in identifying dementia phases from MRI and distinguishing Parkinson's disease through imaging biomarkers of atrophy.^[128]^[129]^[130]^[131]^[132]

Treatment and Prevention

Treatment of atrophy depends on the underlying cause, such as disuse, malnutrition, hormonal deficiencies, or disease-related factors, with strategies aimed at reversing muscle loss, stimulating protein synthesis, and restoring function. Exercise therapy, particularly resistance training, serves as a primary intervention for disuse atrophy, promoting muscle hypertrophy through activation of the mTOR signaling pathway, which enhances protein synthesis and mitigates age-related losses in older adults.^[133]^[134] Studies demonstrate that resistance training can robustly stimulate muscle protein synthesis and counteract atrophy, with protocols involving at least twice-weekly sessions showing significant improvements in muscle mass and strength.^[135]^[136] Nutritional interventions play a crucial role in addressing atrophy linked to malnutrition or inadequate protein intake, focusing on essential amino acids to bolster muscle protein synthesis. Branched-chain amino acids, especially leucine at doses of 3-4 g per meal, act as potent triggers for mTOR activation, helping to preserve lean mass during periods of inactivity and supporting recovery in older adults.^[137]^[138] Supplementation with leucine-enriched nutrients has been shown to enhance anabolic responses, particularly in sarcopenic individuals, by directly stimulating skeletal muscle anabolism independent of overall caloric intake.^[139]^[140] Pharmacological approaches target specific pathways in severe cases, such as cachexia associated with chronic diseases. Anabolic steroids, including testosterone derivatives, have been used to counteract muscle wasting by increasing lean body mass and reducing fat in patients with cachexia, though their application requires careful monitoring due to potential side effects.^[141]^[142] Myostatin inhibitors like bimagrumab, a monoclonal antibody blocking activin type II receptors, have demonstrated efficacy in clinical trials by accelerating muscle volume recovery and increasing lean mass while decreasing fat mass in conditions like sarcopenia and disuse atrophy.^[143]^[144] Emerging GLP-1 receptor agonists, used in obesity management, show potential as of 2025 to preserve muscle mass during weight loss, improving the quality of fat reduction and addressing atrophy risks in metabolic disorders.^[145] For reproductive system atrophy, such as postmenopausal vaginal atrophy, local estrogen therapy effectively relieves symptoms and restores tissue integrity in 80-90% of cases by promoting epithelial proliferation and improving lubrication.^[146]^[147] Hormone replacement therapy addresses endocrine-related atrophy, particularly in hypogonadism where low testosterone contributes to muscle loss. Testosterone supplementation in hypogonadal men increases muscle mass, strength, and overall body composition, alleviating symptoms of wasting by enhancing anabolic processes.^[148]^[149] This therapy is indicated for confirmed deficiencies, with benefits including improved exercise tolerance and reduced fatigue in older patients.^[150] Prevention strategies emphasize proactive measures to avert atrophy progression, especially in at-risk populations like the elderly or post-surgical patients. Early mobilization following surgery minimizes disuse atrophy by reducing complications, accelerating functional recovery, and preserving muscle strength through timely physical activation.^[151]^[152] In older adults, a balanced diet rich in high-quality proteins (1.0-1.2 g/kg body weight/day), fruits, and vegetables supports muscle maintenance and mitigates sarcopenia by optimizing nutrient intake for protein synthesis and antioxidant protection.^[153]^[154] For conditions like spinal muscular atrophy, recent 2025 advancements include muscle-targeting therapies in clinical trials improving motor function and a high-dose regimen of nusinersen approved in some regions, enhancing treatment options for neurogenic atrophy. For denervation atrophy resulting from nerve injuries, surgical options like nerve grafts provide a means to restore innervation and prevent irreversible muscle degeneration. Autologous nerve grafts, such as from the sural nerve, bridge gaps in damaged nerves, enabling axonal regeneration and functional reinnervation when direct repair is not feasible.^[155]^[156] These interventions, often combined with postoperative rehabilitation, aim to limit atrophy and improve long-term outcomes in peripheral nerve injuries.^[157]

Research and Future Directions

Current Research

Recent epidemiological studies have highlighted the global burden of atrophy-related conditions, such as sarcopenia, which affects approximately 10% of adults over 60 years according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria.^[158] A 2025 meta-analysis reported prevalence rates ranging from 10% to 41.2% in older populations, varying by diagnostic methods and influenced by factors like sex and region.^[159] These findings underscore the increasing societal impact of sarcopenia as populations age, with higher rates observed in men (up to 16.36%) compared to women (7.93%) in community-based cohorts.^[160] Research into atrophy mechanisms has increasingly focused on the gut-muscle axis, particularly the role of the microbiome in cachexia and sarcopenia. A 2024 clinical trial demonstrated that modulating the gut microbiome through interventions like short-chain fatty acid (SCFA)-producing bacteria improved muscle function and reduced atrophy in aging models by enhancing microbial diversity and metabolite production.^[161] Similarly, studies from 2024 and 2025 have shown that butyrate, a key microbial metabolite, inhibits cachexia-induced muscle wasting by disrupting gut microbiota dysbiosis associated with cancer and chronic diseases.^[162] These findings suggest that gut microbiota shifts contribute to muscle and adipose tissue loss, opening avenues for microbiome-targeted interventions.^[163] Advances in genetic screening using CRISPR/Cas9 technology have enhanced understanding of atrophy in muscular dystrophies. Since 2023, CRISPR models for Duchenne muscular dystrophy (DMD) have facilitated the creation of precise animal models, enabling the study of genetic mutations and their role in muscle atrophy pathways.^[164] Comprehensive reviews of these applications highlight how genome editing strategies target dystrophin gene corrections, identifying novel regulatory elements involved in atrophy progression.^[165] Ongoing trials, including those reported in 2025, have shown stable genome editing in humanized mouse models, advancing therapeutic potential for dystrophy-associated atrophy.^[166] Longitudinal cohort studies, such as extensions of the Framingham Heart Study, have revealed the impact of lifestyle factors on brain atrophy rates. Analyses from the Framingham Heart Study indicate that higher levels of light-intensity physical activity are associated with larger brain volumes, equivalent to 1.1 years less brain aging per additional hour of activity, thereby mitigating atrophy in aging populations.^[167] Social support and reduced sedentary behavior have also been linked to preserved medial temporal lobe volume, reducing atrophy-related cognitive decline.^[168] Secular trends in Framingham participants born between 1930 and 1970 show improving brain volumes, attributed to enhanced early-life lifestyle and environmental factors.^[169] The legacy of COVID-19 has prompted investigations into its long-term effects on atrophy, with 2025 studies linking long COVID to accelerated muscle wasting. Research on ICU survivors with acute respiratory distress syndrome due to COVID-19 demonstrates persistent muscle loss trajectories, with disease severity influencing atrophy rates up to one year post-infection.^[170] Meta-analyses from 2025 further associate long COVID with neurocognitive impairments, including brain atrophy risks through persistent inflammation and reduced physical function.^[171] Funding trends for atrophy research reflect post-pandemic challenges, with NIH grants facing significant reductions. In 2025, NIH awarded 37% fewer neuroscience-related grants, including those targeting brain atrophy, compared to prior years, amid broader cuts totaling billions in research funding. These reductions have led to the termination of 383 clinical trials by mid-2025, impacting over 74,000 participants in studies including those on muscle and neural atrophy.^[172]^[173] These reductions, including a cap on indirect costs at 15%, have impacted ongoing studies on muscle and neural atrophy mechanisms.^[174]

Emerging Therapies

Emerging therapies for atrophy encompass a range of innovative approaches aimed at addressing the underlying molecular and cellular deficits in various tissues, particularly in conditions like Duchenne muscular dystrophy (DMD), Parkinson's disease, and age-related muscle wasting. These strategies leverage advances in gene delivery, cellular transplantation, epigenetic modulation, targeted drug delivery, and computational modeling to potentially halt or reverse atrophic processes, though many remain in preclinical or early clinical stages. Gene therapy using adeno-associated virus (AAV) vectors to deliver micro-dystrophin represents a promising avenue for treating DMD-associated muscle atrophy. In the phase 3 EMBARK trial (NCT05096221), delandistrogene moxeparvovec (an AAV8-based therapy) was evaluated in ambulatory boys with DMD, demonstrating micro-dystrophin expression in muscle biopsies, alongside secondary improvements in motor function metrics.^[175] Despite not meeting the primary endpoint for North Star Ambulatory Assessment score change, the therapy preserved certain functional aspects, with post-hoc analyses indicating up to 20% relative preservation in stride velocity over 52 weeks compared to placebo.^[176] Similarly, RGX-202, an AAVrh10-microdystrophin therapy from REGENXBIO, showed positive interim data from the phase 1/2 AFFINITY DUCHENNE trial, including enhanced functional outcomes and micro-dystrophin expression in DMD patients.^[177] These developments highlight AAV gene therapies' potential to mitigate progressive muscle atrophy, though cardiac safety concerns and variable expression levels persist.^[178] Stem cell-based interventions, particularly with mesenchymal stem cells (MSCs), offer neuroprotective effects against neural atrophy in Parkinson's disease models. Preclinical studies demonstrate that MSCs, when transplanted intracerebrally or intravenously, secrete neurotrophic factors that protect dopaminergic neurons and reduce neurodegeneration, leading to 10-15% less volume loss in affected brain regions such as the substantia nigra in rodent models.^[179] For instance, hypoxia-preconditioned olfactory mucosa MSCs improved neural recovery and limited atrophy in Parkinson's animal models by modulating inflammation and promoting neuronal survival.^[180] Human trials are ongoing, with MSCs showing feasibility in slowing motor decline and atrophy progression, though challenges include limited blood-brain barrier crossing and long-term engraftment.^[181] In pharmacogenomics, histone deacetylase (HDAC) inhibitors are being explored to target FOXO transcription factors, which regulate muscle regeneration and atrophy pathways. Broad-spectrum HDAC inhibitors like panobinostat induce nuclear translocation of FOXO1 and FOXO3a, upregulating pro-autophagic and regenerative genes while suppressing inflammatory responses in skeletal muscle cells.^[182] This modulation counters FOXO-mediated atrophy signals, promoting muscle fiber repair in pharmacogenomic models of disuse and aging-related wasting, with preclinical data showing enhanced myogenic differentiation.^[183] Class I HDACs, such as HDAC1, directly activate FOXO for atrophy induction, making selective inhibitors a focal point for personalized therapies based on genetic variants in these pathways.^[184] Nanotechnology enables precise drug delivery for localized anti-atrophy treatments, particularly in vaginal tissues affected by postmenopausal atrophy. Pluronic F127-coated estradiol nanosuspensions, administered vaginally, increase estradiol bioavailability and tissue penetration, reducing atrophic changes like epithelial thinning by enhancing local hormone levels without systemic side effects.^[185] Polymeric nanoparticles and liposomes further support sustained release of anti-atrophic agents, improving mucosal integrity and hydration in preclinical vaginal models.^[186] These systems address atrophy's role in genitourinary syndrome, offering targeted efficacy with minimal off-target exposure.^[187] AI-driven personalization is advancing through predictive models for atrophy risk in aging populations, with 2025 prototypes integrating multi-omics data to forecast sarcopenia and neural decline. Machine learning algorithms, such as those using comprehensive health check-up datasets, predict biological age and atrophy susceptibility with high accuracy, enabling tailored interventions like exercise regimens to mitigate 15-20% of projected muscle loss.^[188] These models, often employing deep learning for digital twins, identify at-risk individuals in age-related cohorts, supporting precision geriatrics.^[189] Despite these advances, emerging therapies face significant challenges, including off-target effects in ubiquitin-proteasome system (UPS) modulation, where inhibitors like bortezomib can inadvertently degrade non-atrophic proteins, exacerbating toxicity in muscle and neural tissues.^[190] Ethical concerns also arise in enhancement therapies, such as gene editing for non-pathological atrophy prevention, raising issues of equitable access, long-term safety, and the blurring of therapeutic versus augmentative boundaries in aging populations.^[191] Ongoing research emphasizes the need for refined targeting to balance efficacy and risk.

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Duchenne muscular dystrophy: disease mechanism and therapeutic ...
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Polymyositis and dermatomyositis: Disease spectrum and ... - NIH
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Trabecular bone loss occurs preferentially among the trabeculae that get the least stress. ... disuse osteopenia without an intact blood supply to that bone.
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The clinician's guide to prevention and treatment of osteoporosis
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Fibrillation potential amplitude to quantitatively assess denervation ...
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Working model of how gut microbes contribute to muscle and adipose tissue wasting with cachexia. The gastrointestinal mucosa plays a vital role not only in ...
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CRISPR-mediated generation and comprehensive phenotyping of ...
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Stem cells therapy in neurodegenerative and neuroimmune diseases
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