Understanding What Is Muscle Wasting Mechanisms Causes Interventions

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Muscle wasting represents a critical decline in skeletal muscle mass and function, profoundly impacting mobility, quality of life, and long-term health. Beyond the visible deterioration of muscle tissue, this condition disrupts metabolic balance, accelerates aging, and exacerbates complications in chronic diseases such as cancer, diabetes, and neurological disorders. While often overlooked in early stages, its progression can lead to severe functional impairments, underscoring the need for precise diagnosis and targeted intervention strategies.

The physiological underpinnings of muscle wasting involve a complex interplay of hormonal imbalances, inflammatory pathways, and mitochondrial dysfunction. Conditions like sarcopenia—age-related muscle loss—and cachexia, associated with severe illnesses, share distinct yet overlapping mechanisms, from protein degradation via the ubiquitin-proteasome system to impaired anabolic signaling. Understanding these pathways is essential for developing effective therapeutic approaches, ranging from resistance-based exercise regimens to emerging pharmacological treatments. This discussion explores the scientific foundations, diagnostic tools, and evidence-based interventions that address muscle wasting across diverse populations.

what is muscle wasting

Medical Classification and Biochemical Mechanisms of Muscle Wasting

Muscle wasting encompasses a spectrum of pathological conditions characterized by the progressive loss of skeletal muscle mass and function, driven by distinct etiological pathways. While often conflated, muscle wasting manifests in clinically and mechanistically distinct forms—cachexia, sarcopenia, and atrophy—each with unique diagnostic criteria, underlying causes, and therapeutic implications. Understanding these distinctions is critical for targeted interventions, as their progression and response to treatment differ significantly. Below, the classification is systematically outlined, followed by an exploration of the molecular pathways governing protein degradation in muscle tissue.

Classification of Muscle Wasting: Cachexia, Sarcopenia, and Atrophy

Muscle wasting is categorized based on onset, reversibility, and associated systemic conditions. Cachexia represents a severe, treatment-resistant syndrome linked to chronic illnesses, whereas sarcopenia is age-related and often reversible with intervention. Atrophy, though overlapping in mechanisms, is typically localized or secondary to disuse. The following table summarizes their defining features, facilitating differential diagnosis and therapeutic stratification.

  • Muscle depletion (appendicular lean mass loss >2 standard deviations below normal).
  • Fatigue, weakness, and reduced physical performance.
  • Anorexia or altered taste perception.
  • Biochemical markers: Elevated C-reactive protein (CRP), albumin <3.2 g/dL.
    • Type Primary Causes Key Symptoms Diagnostic Methods
    Cachexia
    • Chronic inflammatory diseases (e.g., cancer, heart failure, COPD, rheumatoid arthritis).
    • Systemic inflammation via pro-inflammatory cytokines (TNF-α, IL-1, IL-6).
    • Metabolic dysregulation (insulin resistance, increased proteolysis).
    • Reduced food intake (anorexia) and altered metabolism.
    • Rapid, unintentional weight loss (>5% in 6 months).
    • Body composition analysis (DEXA, bioelectrical impedance analysis).
    • Handgrip strength testing (<20 kg in men, <15 kg in women).
    • 6-minute walk test (distance <300 meters).
    • Serum biomarkers (CRP, prealbumin, pro-inflammatory cytokines).
    • Exclusion of other causes (e.g., malnutrition, thyroid disorders).
    Sarcopenia
    • Primary: Aging-related (intrinsic loss of muscle mass and function).
    • Secondary: Associated with comorbidities (e.g., diabetes, obesity, physical inactivity).
    • Neurodegenerative diseases (e.g., Parkinson’s, ALS).
    • Hormonal deficiencies (testosterone, growth hormone, IGF-1).
    • Gradual reduction in muscle strength and physical performance.
    • Slower gait speed (<0.8 m/s).
    • Difficulty with activities of daily living (e.g., rising from a chair).
    • Increased risk of falls and fractures.
    • Preserved or slightly reduced body weight (unlike cachexia).
    • Muscle mass assessment (appendicular skeletal muscle mass/height² <20 kg/m² in men, <15 kg/m² in women).
    • Strength testing (grip strength <27 kg in men, <16 kg in women).
    • Physical performance (e.g., Short Physical Performance Battery).
    • Dual-energy X-ray absorptiometry (DEXA) or computed tomography (CT).
    Muscle Atrophy
    • Disuse (immobilization, bed rest, spaceflight).
    • Denervation (peripheral nerve injury, spinal cord injury).
    • Localized trauma or ischemia.
    • Neuromuscular disorders (e.g., muscular dystrophy).
    • Endocrine disorders (hyperthyroidism, Cushing’s syndrome).
    • Asymmetrical or localized muscle shrinkage.
    • Weakness in affected muscle groups (e.g., foot drop in peroneal nerve injury).
    • Reduced muscle tone and reflexes (in denervation atrophy).
    • Possible muscle cramps or fasciculations.
    • No systemic symptoms (unlike cachexia).
    • Clinical examination (muscle symmetry, strength grading).
    • Electromyography (EMG) for neurogenic atrophy.
    • MRI/CT to assess muscle volume and fatty infiltration.
    • Laboratory tests (creatine kinase levels in dystrophies).
    • Exclusion of systemic causes (e.g., thyroid function tests).

    Biochemical Pathways in Muscle Protein Degradation

    The loss of muscle protein in wasting conditions is governed by dysregulated proteolytic systems, primarily the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway. These pathways, under normal conditions, maintain cellular protein homeostasis by tagging and degrading damaged or unnecessary proteins. However, in muscle wasting, their activity becomes aberrantly upregulated, leading to excessive myofibrillar protein breakdown. Below are the key molecular mechanisms:
    The ubiquitin-proteasome system (UPS) mediates the ATP-dependent degradation of ubiquitinated proteins. In muscle wasting:
  • E3 ligases (e.g., MuRF1, atrogin-1/MAFbx) are upregulated by inflammatory signals (NF-κB, FoxO transcription factors) and glucocorticoids.
  • Ubiquitin tags target myofibrillar proteins (e.g., troponin, myosin heavy chain) for degradation by the 26S proteasome.
  • Autophagy (macroautophagy) sequesters cytoplasmic components (e.g., mitochondria, protein aggregates) in autophagosomes, which fuse with lysosomes for degradation.
  • Lysosomal enzymes (cathepsins) further break down proteins, with their activity often elevated in cachexia.
  • Mitochondrial dysfunction (e.g., reduced PGC-1α) impairs energy production, exacerbating proteolysis.
    • The interplay between these pathways is further modulated by:
  • Inflammatory cytokines (TNF-α, IL-6) activating NF-κB, which induces MuRF1 and atrogin-1 expression.
  • Insulin/IGF-1 resistance, reducing mTORC1 signaling and promoting autophagy.
  • Oxidative stress, activating FoxO transcription factors and enhancing UPS activity.
  • Hormonal imbalances (e.g., low testosterone, high cortisol) shifting metabolism toward catabolism.

    • Example in Cachexia:
    In cancer-associated cachexia, tumor-derived factors (e.g., lactates, proteolysis-inducing factor) directly stimulate muscle UPS activity, while systemic inflammation amplifies FoxO-mediated proteolysis. Concurrently, autophagy is dysregulated, leading to mitochondrial dysfunction and further energy deficits.

    Example in Sarcopenia:
    Aging reduces satellite cell activity and insulin-like growth factor 1 (IGF-1), impairing muscle protein synthesis while increasing basal autophagy and UPS activity. Chronic low-grade inflammation ("inflammaging") further exacerbates proteolysis via NF-κB.

    Physiological Mechanisms and Pathways in Muscle Wasting

    Muscle wasting, or sarcopenia, arises from a complex interplay of hormonal imbalances, inflammatory responses, and cellular dysfunction. These mechanisms disrupt anabolic signaling, impair mitochondrial efficiency, and accelerate proteolysis, ultimately leading to muscle fiber atrophy. Below, the molecular pathways—including hormonal disruptions, cytokine-mediated inflammation, and neuro-mitochondrial interactions—are examined in detail to elucidate their roles in accelerating muscle degradation.

    Hormonal Disruptions and Molecular Interactions in Muscle Wasting

    Hormonal imbalances significantly contribute to muscle wasting by altering protein turnover, satellite cell activity, and metabolic efficiency. Key hormones—cortisol, testosterone, and insulin-like growth factor 1 (IGF-1)—mediate these effects through distinct but interconnected pathways.
    Cortisol (glucocorticoid) exerts catabolic effects by:
    1. Upregulating ubiquitin-proteasome system (UPS) activity via glucocorticoid receptor (GR)-mediated transcription of atrogin-1 and MuRF-1, E3 ligases that tag muscle proteins for degradation.
    2. Inhibiting IGF-1/PI3K/AKT/mTOR signaling, reducing muscle protein synthesis (MPS) by suppressing ribosomal S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E) phosphorylation.
    3. Enhancing autophagy through FOXO3a activation, diverting cellular resources toward energy production rather than maintenance.
    Testosterone deficiency disrupts muscle homeostasis via:
  • Reduced activation of androgen receptors (AR), leading to decreased transcription of anabolic genes (myogenin, myostatin inhibitors).
  • Impaired satellite cell proliferation due to disrupted Notch signaling and Pax7 downregulation.
  • Altered mitochondrial biogenesis via reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression, exacerbating oxidative stress.

    • IGF-1 deficiency disrupts:

  • PI3K/AKT/mTOR pathway, critical for MPS initiation and elongation factor 2 (eEF2) activity.
  • Satellite cell quiescence-to-proliferation transition via reduced PI3K/AKT/FOXO signaling.
  • Collagen synthesis and extracellular matrix remodeling, impairing muscle repair.
    • Key Interaction:
    Cortisol and low testosterone synergistically suppress IGF-1 signaling, creating a feedback loop where reduced anabolic stimuli (IGF-1) and elevated catabolic stimuli (cortisol) amplify muscle degradation.

    Chronic Inflammation and Disruption of Muscle Protein Synthesis and Repair

    Chronic inflammation, driven by pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), disrupts muscle homeostasis by:
    1. Inhibiting MPS through NF-κB pathway activation, which:
  • Phosphorylates IκBα, releasing NF-κB to translocate to the nucleus.
  • Suppresses mTORC1 signaling via TSC2 (tuberous sclerosis complex 2) activation, reducing ribosomal protein S6 (S6) and 4E-BP1 phosphorylation.
  • Upregulates SOCS3, a negative regulator of IGF-1/PI3K/AKT signaling.
    • 2. Enhancing proteolysis via:
  • NF-κB-mediated induction of atrogenes (atrogin-1, MuRF-1), accelerating UPS activity.
  • JAK/STAT pathway activation by IL-6, promoting FOXO transcription factors to transcribe ubiquitin ligases.
    • 3. Impairing satellite cell function through:
  • TNF-α-induced apoptosis via caspase-3 activation.
  • IL-6-mediated suppression of Pax7, reducing myogenic precursor cell proliferation.
    • Cytokine Cross-Talk:
    TNF-α and IL-6 create a pro-inflammatory milieu that:
  • Downregulates myostatin inhibitors (e.g., Follistatin), increasing myostatin’s inhibitory effect on muscle growth.
  • Induces indoleamine 2,3-dioxygenase (IDO), depleting tryptophan and reducing muscle protein synthesis.
    • Step-by-Step Disruption of Repair Mechanisms:
    1. Satellite Cell Dysfunction:
  • Chronic inflammation reduces Pax7+ cell numbers via TNF-α-mediated apoptosis and IL-6-induced differentiation block.
  • Wnt/β-catenin signaling is suppressed, impairing regenerative niche maintenance.
    • 2. Extracellular Matrix (ECM) Remodeling Failure:
  • MMP/TIMP imbalance (e.g., elevated MMP-9) degrades ECM, disrupting mechanical signaling (e.g., integrins).
  • Collagen cross-linking is impaired, reducing muscle stiffness and force transmission.
    • 3. Mitochondrial Dysfunction:
  • TNF-α and IL-1β reduce PGC-1α expression, impairing oxidative phosphorylation and increasing reactive oxygen species (ROS).
  • ROS accumulation further activates NF-κB, creating a vicious cycle of inflammation and mitochondrial damage.

    • Interplay Between Neural Signals, Mitochondrial Dysfunction, and Muscle Fiber Loss

    The neuro-mitochondrial axis is critical in muscle wasting, where denervation, metabolic dysfunction, and fiber-type transitions accelerate atrophy. Below is a plaintext flowchart of the interplay:

    ```
    [Denervation/Neural Atrophy]
    │
    ├── Reduced Motor Unit Activation → ↓ Mechanical Loading → ↓ IGF-1/AKT/mTOR (via stretch-activated channels)
    │ │
    │ └── Disuse Atrophy Pathway:
    │ - ↑ Atrogenes (atrogin-1, MuRF-1) via FOXO3a activation
    │ - ↓ Satellite cell fusion due to lack of Notch/Dll1 signaling
    │
    └── Altered Neural Signaling → Mitochondrial Dysfunction:
    │
    ├── ↓ Neuregulin-1 (NRG1) → ↓ Mitochondrial biogenesis (PGC-1α suppression)
    │ │
    │ └── ↑ ROS production → NF-κB activation → Cytokine release (TNF-α, IL-6)
    │
    └── ↓ Calcium Handling (via ryanodine receptor dysfunction) → ↓ Mitochondrial Ca²⁺ uptake → ↓ ATP production
    │
    └── Fiber-Type Transition:

  • Type II (fast-twitch) → Type I (slow-twitch) shift (due to ↓ Ca²⁺/Calmodulin-dependent kinase IV (CaMKIV))
  • ↓ Myosin heavy chain (MHC) expression → Reduced force generation
    • ```

    Key Mechanisms:
    1. Denervation-Induced Mitochondrial Stress:

  • Reduced NRG1 (secreted by motor neurons) leads to ↓ TFAM (mitochondrial transcription factor A), impairing mtDNA replication.
  • ↑ Dynamin-related protein 1 (Drp1) activity fragments mitochondria, increasing mitochondrial permeability transition pore (mPTP) opening and apoptosis.
    • 2. Fiber-Specific Atrophy:
  • Type II fibers (fast-twitch) are more susceptible due to:
  • Higher oxidative stress (↑ ROS from impaired ETC).
  • ↓ Myostatin inhibition (via ↓ activin receptor signaling).
  • Type I fibers (slow-twitch) undergo ↓ oxidative capacity due to ↓ PGC-1α coactivators.
    • 3. Neuroinflammation Feedback Loop:
  • Denervated muscle releases chemokines (CXCL1, CCL2), attracting macrophages that secrete TNF-α/IL-1β, further damaging mitochondria.
    • Critical Thresholds:
  • >30% denervation triggers irreversible fiber-type transition and mitochondrial loss.
  • ↑ TNF-α:IGF-1 ratio > 2.5 correlates with >50% reduction in MPS within 48 hours.

    • what is muscle wasting - Ilustrasi 2

    Common Causes and Risk Factors of Muscle Wasting

    Muscle wasting, or sarcopenia, represents a progressive loss of muscle mass and function that impairs mobility, independence, and overall quality of life. While aging is a primary contributor, the condition arises from a complex interplay of physiological, pathological, and lifestyle-related factors. Understanding these causes and identifying high-risk populations is essential for targeted prevention and intervention strategies. This section categorizes the primary etiologies of muscle wasting, examines vulnerable demographic groups, and compares the impact of key nutritional deficiencies on muscle maintenance.

    Primary Causes and Mechanisms of Muscle Wasting

    Muscle wasting results from an imbalance between muscle protein synthesis (MPS) and breakdown (MPB), exacerbated by systemic or localized disruptions. The following categories encapsulate the most significant contributors, each with distinct mechanistic pathways.
    Aging induces irreversible declines in muscle mass and strength, primarily through:
  • Anabolic Resistance: Reduced sensitivity to amino acids (e.g., leucine) and insulin, impairing MPS.
  • Hormonal Shifts: Lower testosterone, growth hormone (GH), and insulin-like growth factor 1 (IGF-1) levels accelerate muscle degradation.
  • Neuromuscular Junction Decline: Loss of motor neurons (up to 50% by age 80) reduces neural stimulation of muscle fibers.
  • Mitochondrial Dysfunction: Accumulation of oxidative damage and reduced ATP production limit muscle endurance and repair.
  • Chronic Low-Grade Inflammation: Elevated pro-inflammatory cytokines (e.g., TNF-α, IL-6) promote proteolysis via the ubiquitin-proteasome system (UPS).

    • 2. Nutritional Deficiencies

    Inadequate intake or absorption of critical nutrients disrupts muscle metabolism and repair. Key deficiencies include:
  • Protein: Essential for MPS; insufficient intake (<0.8–1.2 g/kg body weight/day) fails to stimulate muscle protein synthesis, particularly in older adults.
  • Vitamin D: Deficiency (<20 ng/mL) reduces muscle protein synthesis by impairing calcium absorption and IGF-1 signaling.
  • Omega-3 Fatty Acids (EPA/DHA): Low levels (<1% of total fatty acids) increase inflammation and reduce satellite cell activation, critical for muscle regeneration.
  • Magnesium and Zinc: Deficiencies impair muscle contraction, DNA/RNA synthesis, and antioxidant defense, exacerbating age-related atrophy.
  • Vitamin B12 and Folate: Deficiencies disrupt methylation cycles, leading to impaired muscle energy metabolism and neural dysfunction.

    • 3. Chronic Diseases and Systemic Conditions

    Underlying pathologies trigger muscle wasting through metabolic, inflammatory, or neuroendocrine pathways. Notable examples include:
  • Cardiovascular Diseases: Heart failure reduces blood flow to muscles, while medications (e.g., beta-blockers) may suppress anabolic signaling.
  • Chronic Obstructive Pulmonary Disease (COPD): Hyperinflation and dyspnea limit physical activity, while systemic inflammation (e.g., elevated CRP) accelerates proteolysis.
  • Diabetes (Type 1 and 2): Insulin resistance impairs glucose uptake in muscles, while hyperglycemia promotes advanced glycation end-products (AGEs), cross-linking muscle proteins and reducing flexibility.
  • Chronic Kidney Disease (CKD): Uremia induces oxidative stress and metabolic acidosis, while protein-restricted diets (historically prescribed) further deplete muscle reserves.
  • Cancer Cachexia: Tumor-derived factors (e.g., myostatin, TNF-α) and systemic inflammation override normal regulatory pathways, leading to rapid muscle degradation despite adequate caloric intake.

    • 4. Physical Inactivity and Disuse Atrophy

    Prolonged immobility or sedentary behavior directly reduces muscle load, triggering:
  • Reduced Mechanical Stimulation: Disuse atrophy begins within 48 hours of inactivity, with up to 5% muscle mass loss per week in severe cases (e.g., bed rest).
  • Denervation: Immobilization reduces neural input, accelerating fiber-type transitions (e.g., Type II to Type I) and atrophy.
  • Metabolic Shifts: Increased reliance on oxidative metabolism in inactive muscles reduces overall mass and strength.

    • 5. Inflammatory and Autoimmune Disorders

    Chronic inflammation disrupts muscle homeostasis through:
  • Cytokine-Mediated Proteolysis: TNF-α and IL-1 activate the UPS and autophagy, degrading myofibrillar proteins.
  • Satellite Cell Dysfunction: Persistent inflammation impairs muscle stem cell proliferation, hindering repair.
  • Examples: Rheumatoid arthritis, systemic lupus erythematosus (SLE), and sepsis-associated myopathy.

    • 6. Endocrine Disorders

    Hormonal imbalances alter muscle metabolism and protein turnover:
  • Hyperthyroidism: Excess thyroid hormone (T3/T4) increases proteolysis via ubiquitin ligases (e.g., MuRF1, Atrogin-1).
  • Hypogonadism: Low testosterone reduces IGF-1 and MPS, while estrogen deficiency in postmenopausal women accelerates sarcopenia.
  • Cushing’s Syndrome: Chronic cortisol excess promotes muscle catabolism and insulin resistance.

    • 7. Pharmacological Induced Muscle Wasting

    Certain medications accelerate muscle loss through metabolic or neurotoxic effects:
  • Glucocorticoids: Prednisone and dexamethasone induce myopathy via increased proteolysis and reduced protein synthesis.
  • Chemotherapy Agents: Vincristine and doxorubicin damage muscle fibers and impair satellite cell function.
  • Antiretrovirals (e.g., Zidovudine): Associated with mitochondrial dysfunction in HIV patients.

    • High-Risk Populations for Muscle Wasting

    Specific demographic and clinical groups exhibit heightened vulnerability to muscle wasting due to compounding physiological and socioeconomic factors. The following populations require targeted screening and intervention.
  • Prevalence: Affects >50% of adults aged 80+, with severe cases leading to frailty and institutionalization.
  • Unique Vulnerabilities:
  • Reduced Anabolic Response: Older adults require ~30–40% more protein than younger individuals to stimulate MPS.
  • Polypharmacy: Concurrent use of medications (e.g., statins, beta-blockers) may exacerbate muscle loss.
  • Sarcopenic Obesity: Coexistence of muscle loss and fat gain impairs mobility and metabolic health.
  • Key Interventions: High-protein diets (1.2–1.6 g/kg/day), resistance training, and vitamin D supplementation.

    • 2. Cancer Patients (Cachexia)

  • Prevalence: Up to 80% of advanced cancer patients experience cachexia, with muscle loss correlating with poorer survival.
  • Unique Vulnerabilities:
  • Tumor-Derived Factors: Myostatin and proteolysis-inducing factor (PIF) override normal muscle regulatory pathways.
  • Treatment Side Effects: Chemotherapy and radiation induce oxidative stress and muscle fiber damage.
  • Anorexia: Reduced appetite and nausea further limit nutrient intake.
  • Key Interventions: Anti-inflammatory diets, exercise (where tolerated), and pharmacological agents (e.g., ghrelin agonists).

    • 3. Bedridden and Critically Ill Patients

  • Prevalence: ICU-acquired weakness affects ~25% of mechanically ventilated patients, with muscle loss exceeding 10% per week.
  • Unique Vulnerabilities:
  • Immobilization: Disuse atrophy progresses rapidly due to lack of mechanical load.
  • Systemic Inflammation: Sepsis and trauma trigger excessive cytokine release (e.g., IL-6, TNF-α).
  • Metabolic Dysregulation: Hyperglycemia and insulin resistance impair muscle protein synthesis.
  • Key Interventions: Early mobilization, nutritional support (enteral/parenteral), and electrical muscle stimulation (EMS).

    • 4. Individuals with Chronic Kidney Disease (CKD)

  • Prevalence: Up to 30% of CKD patients develop severe muscle wasting, worsening with dialysis dependence.
  • Unique Vulnerabilities:
  • Uremic Toxins: Accumulation of indoxyl sulfate and p-cresol disrupts mitochondrial function.
  • Acidosis: Chronic metabolic acidosis accelerates protein catabolism.
  • Protein Restriction: Historically prescribed diets limit amino acid availability for MPS.
  • Key Interventions: Dialysis-specific exercise programs, ketoanalogue supplementation, and bicarbonate therapy for acidosis.

    • 5. Patients with Neuromuscular Disorders

  • Examples: Amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and multiple sclerosis (MS).
  • Unique Vulnerabilities:
  • Denervation: Loss of motor neurons leads to rapid fiber atrophy (e.g., ALS patients lose ~10% muscle mass/year).
  • Immobility: Progressive weakness reduces physical activity, exacerbating disuse atrophy.
  • Metabolic Dysregulation: MS patients exhibit reduced mitochondrial efficiency in muscles.
  • Key Interventions: Non-invasive ventilation (for ALS), resistance training (where

    • Diagnostic Approaches and Tools in Muscle Wasting

    Accurate diagnosis of muscle wasting (sarcopenia or cachexia) requires a multimodal approach integrating clinical assessments, laboratory markers, and advanced imaging techniques. Early detection is critical for differentiating between reversible and progressive conditions, guiding targeted interventions, and improving patient outcomes. While no single test confirms muscle wasting, a combination of functional, biochemical, and imaging modalities provides a comprehensive evaluation of muscle integrity, metabolic status, and systemic involvement.

    Diagnostic strategies must balance accessibility, cost, and specificity to ensure applicability across clinical settings. Clinical assessments offer rapid, non-invasive insights into muscle function and mass, though they often lack precision in quantifying severity. Laboratory markers provide biochemical evidence of muscle degradation or systemic inflammation, while imaging techniques deliver objective measurements of muscle atrophy and fat infiltration. Integration of these tools allows clinicians to tailor diagnostic workups to patient presentations, whether in aging populations, chronic disease states, or critical care scenarios.

    Clinical Assessments in Muscle Wasting Evaluation

    Clinical assessments form the foundation of muscle wasting diagnosis, offering practical and reproducible methods to evaluate muscle function and mass. These tools are particularly valuable in primary care and resource-limited settings, where advanced imaging or laboratory tests may not be readily available. However, their limitations—such as subjectivity, variability, and lack of specificity—necessitate supplementation with objective diagnostic modalities.

    Functional Performance Tests
    Functional assessments directly measure muscle strength and physical capability, serving as early indicators of sarcopenia or cachexia. The most widely used tests include:

  • Handgrip Dynamometry: Evaluates upper-body muscle strength, with thresholds for sarcopenia often set at <20 kg for women and <30 kg for men. Low grip strength correlates with increased mortality and functional decline, particularly in older adults.
  • Chair Stand Test (30-second sit-to-stand): Assesses lower-body strength and endurance. A count of <10 repetitions in 30 seconds is indicative of sarcopenia in adults over 60.
  • Timed Up and Go (TUG) Test: Measures mobility and balance, with times >12 seconds suggesting muscle weakness and fall risk.
  • Short Physical Performance Battery (SPPB): Combines balance, gait speed, and chair stand tests to provide a composite score (0–12), where scores <8 predict adverse outcomes.
    • Limitations of Functional Tests:
  • Floor and ceiling effects: May fail to detect subtle changes in high-functioning or severely impaired individuals.
  • Inter-observer variability: Technique-dependent measurements (e.g., grip strength positioning) can skew results.
  • Lack of specificity: Weakness may stem from neurological, cardiovascular, or joint disorders rather than muscle wasting alone.
    • Body Composition Assessments
    These tools estimate muscle mass and fat distribution, though they often rely on surrogate markers rather than direct muscle tissue analysis. Key methods include:
  • Bioelectrical Impedance Analysis (BIA): Uses electrical resistance to estimate fat-free mass, with limitations in fluid status (e.g., edema, dehydration) and accuracy in obese or amputee patients.
  • Skinfold Calipers: Measures subcutaneous fat thickness at standardized sites (e.g., triceps, biceps) to estimate body fat percentage. Prone to user error and fails to assess visceral fat or intramuscular fat.
  • Circumference Measurements: Includes mid-arm muscle circumference (MAMC) and calf circumference, which correlate with muscle mass but are influenced by edema and subcutaneous fat.
  • Waist-to-Hip Ratio (WHR): Indicates central adiposity, a risk factor for sarcopenic obesity, but does not directly measure muscle.
    • Practical Considerations for Clinical Use:
  • Combination approaches: Pairing grip strength with BIA or circumference measurements improves diagnostic accuracy.
  • Age-specific cutoffs: Normative data must account for sex, ethnicity, and age (e.g., lower thresholds for sarcopenia in elderly populations).
  • Dynamic monitoring: Serial assessments are more informative than single-timepoint evaluations for tracking progression or response to therapy.

    • Laboratory Markers of Muscle Degradation

    Laboratory tests provide biochemical evidence of muscle breakdown, systemic inflammation, or metabolic derangements underlying muscle wasting. While no single marker is definitive, panels of tests can support clinical suspicion and guide differential diagnosis. Markers are categorized into those reflecting muscle damage, protein metabolism, inflammation, and nutritional status.
    Interpretation Guidelines:
  • Elevated markers may indicate active muscle catabolism but can also reflect non-muscle pathologies (e.g., liver disease, infection).
  • Normal ranges vary by laboratory, age, and sex; results should be interpreted in clinical context.
  • Serial measurements are more valuable than isolated values for tracking disease progression or treatment efficacy.
    • Marker Normal Range Wasting Indication
    Creatine Kinase (CK) Male: 38–174 U/L
    Female: 26–140 U/L    		 Moderately elevated (2–5× ULN) suggests muscle injury or inflammation (e.g., rhabdomyolysis, polymyositis). Severe elevation (>10× ULN) may indicate acute muscle necrosis or dystrophy. Note: CK is nonspecific and can be elevated in cardiac or skeletal muscle disorders.
    Creatinine Male: 0.7–1.3 mg/dL
    Female: 0.6–1.1 mg/dL    		 Decreased levels (with normal kidney function) may reflect reduced muscle mass, though creatinine is influenced by diet and hydration. Use in conjunction with estimated glomerular filtration rate (eGFR) to avoid misinterpretation.
    C-Reactive Protein (CRP) <10 mg/L (low risk)
    10–30 mg/L (moderate risk)
    >30 mg/L (high risk)    		 Elevated CRP (>3 mg/L) indicates systemic inflammation, a driver of cachexia in cancer, sepsis, or chronic diseases (e.g., COPD, heart failure). Persistent elevation correlates with poor prognosis.
    Albumin 3.5–5.0 g/dL Hypoalbuminemia (<3.5 g/dL) reflects poor nutritional status or hepatic dysfunction, both contributing to muscle wasting. Note: Albumin is an acute-phase reactant and may be normal in early-stage cachexia.
    Prealbumin (Transthyretin) 15–36 mg/dL Low levels (<15 mg/dL) indicate acute protein-energy malnutrition, often preceding overt muscle wasting. Responds rapidly to nutritional intervention.
    Urea Nitrogen (BUN) 7–20 mg/dL Elevated BUN (with normal creatinine) may suggest increased protein catabolism, though renal function and hydration status must be considered.
    Myostatin Not routinely measured; research focus Elevated levels (in cancer or chronic diseases) inhibit muscle growth and promote atrophy. Emerging as a therapeutic target.
    3-Methylhistidine (3-MH) Not standardized; urine excretion typically 10–20 µmol/day Increased urinary excretion reflects muscle protein breakdown, though it lacks clinical utility due to cost and variability.
    Emerging Biomarkers:
  • MicroRNAs (e.g., miR-21, miR-206): Circulating miRNAs correlate with muscle degradation in cancer cachexia and may serve as non-invasive diagnostic tools.
  • GDF-11 (Growth Differentiation Factor 11): Elevated levels in aging and chronic diseases; linked to muscle stem cell dysfunction.
  • Follistatin: Altered levels in sarcopenia, modulating myostatin activity.

    • Imaging Techniques for Quantifying Muscle Mass Loss

    Advanced imaging provides objective, quantifiable measures of muscle atrophy, fat infiltration, and structural changes associated with muscle wasting. These modalities are gold standards for research and specialized clinical settings but are limited by cost, accessibility, and radiation exposure (where applicable). Proper protocol adherence and standardized analysis are essential for reproducibility.

    Computed Tomography (CT) Scans
    CT scans offer high-resolution cross-sectional images of muscle and fat compartments, enabling precise measurements of muscle area (e.g., psoas, quadriceps) and density. Protocols must standardize slice selection (typically at L3 vertebral level) and use Hounsfield unit (HU) thresholds to differentiate muscle from fat.

    - Protocols:

  • Slice Selection: Axial images

    • what is muscle wasting - Ilustrasi 3

    Intervention Strategies and Therapies in Muscle Wasting

    Muscle wasting, or sarcopenia, represents a progressive loss of muscle mass and function with significant implications for mobility, metabolic health, and quality of life. Effective intervention requires a multimodal approach integrating exercise, pharmacological therapies, and targeted nutritional strategies. Resistance-based interventions remain foundational, while emerging pharmacological agents and precision nutrition offer complementary pathways to mitigate atrophy. This section evaluates evidence-based strategies, comparing their efficacy and mechanistic underpinnings to inform clinical decision-making.

    Exercise-Based Interventions for Muscle Preservation

    Exercise interventions are the cornerstone of muscle-wasting countermeasures due to their ability to stimulate anabolic signaling, improve neuromuscular efficiency, and enhance metabolic resilience. Among the most studied modalities are resistance training (RT), progressive overload (PO), and neuromuscular electrical stimulation (NMES), each demonstrating distinct advantages and limitations in clinical and aged populations.

    Resistance Training (RT) Mechanisms and Efficacy
    RT induces muscle hypertrophy and strength gains through mechanical tension, metabolic stress, and muscle damage, triggering satellite cell activation and protein synthesis via the mTOR (mechanistic target of rapamycin) pathway. Meta-analyses indicate that 8–12 weeks of progressive RT in sarcopenic individuals yields 1–3% increases in muscle mass and 10–30% improvements in strength, with greater effects observed in younger adults compared to elderly populations (Cruz-Jentoft et al., 2019). Key variables include:

  • Exercise selection: Compound movements (e.g., squats, deadlifts) prioritize multi-joint engagement and systemic anabolic responses.
  • Volume and frequency: 2–4 sets per exercise, 2–3 sessions/week, with progressive overload (PO) applied via increased resistance or repetitions.
  • Progression models: Linear (fixed increments), undulating (periodized), or daily undulating (DU) models optimize adaptation by manipulating volume/intensity cycles.

    • Progressive Overload (PO) in Muscle Wasting
    PO refers to the systematic increase in training stimulus to prevent plateaus and sustain hypertrophy. In clinical populations (e.g., cancer cachexia, chronic obstructive pulmonary disease [COPD]), PO protocols incorporating 10–20% weekly load increases or repetition-based progression (e.g., adding 1–2 reps to sets of 8–12) yield superior outcomes compared to static resistance training. A 2021 study in HIV-associated sarcopenia demonstrated that PO RT combined with protein supplementation improved lean mass by 4.5% over 12 weeks (Tang et al., 2021). Critical considerations include:

  • Individualization: Adjustments for frailty (e.g., lower starting loads, higher repetition ranges) to mitigate injury risk.
  • Monitoring fatigue: The Borg Scale (6–20) or OMNI-RES can guide intensity modulation in deconditioned patients.
  • Compliance: Supervised programs enhance adherence, with tele-rehabilitation emerging as a viable alternative for home-based PO RT.

    • Neuromuscular Electrical Stimulation (NMES) in Non-Ambulatory Patients
    NMES delivers electrical impulses to muscles, eliciting contractions independently of voluntary effort. While less effective than RT in healthy individuals, NMES is critical for bedridden or neurologically impaired patients (e.g., spinal cord injury, stroke). Systematic reviews report 1–2% muscle mass gains with 20–30 minutes/day, 5 days/week of NMES, though effects plateau without concurrent nutritional support (Kaminski et al., 2019). Key applications include:

  • Functional electrical stimulation (FES): Targets specific muscle groups (e.g., quadriceps) to improve gait or reduce spasticity.
  • High-frequency NMES (50–100 Hz): Optimizes muscle fiber recruitment, mimicking voluntary contractions.
  • Combination therapies: NMES + RT or blood flow restriction (BFR) enhances anabolic responses in frail elderly by 20–40% (Hughes et al., 2020).
    • Clinical Consideration: NMES should be tailored to muscle group size, with smaller muscles (e.g., biceps) requiring lower currents (20–50 mA) than large muscles (e.g., quadriceps, 80–120 mA). Contraindications include pacemakers, epilepsy, or skin lesions at electrode sites.

    Pharmacological Interventions in Muscle Wasting

    Pharmacological agents address the biochemical pathways underlying muscle atrophy, particularly catabolic excess (e.g., cortisol, pro-inflammatory cytokines) and anabolic deficits (e.g., IGF-1, testosterone). While no single drug reverses sarcopenia, combinations of anabolic steroids, myostatin inhibitors, and selective androgen receptor modulators (SARMs) show promise in specific populations.

    Anabolic Steroids and Testosterone Replacement Therapy (TRT)
    Testosterone deficiency is a modifiable risk factor in age-related and secondary sarcopenia. TRT in hypogonadal men increases muscle mass by 1–3 kg and strength by 10–20% over 6–12 months (Wang et al., 2020). Mechanisms include:

  • Androgen receptor activation: Enhances satellite cell proliferation and IGF-1/Akt/mTOR signaling.
  • Reduction in myostatin: Testosterone downregulates this negative regulator of muscle growth.
  • Clinical protocols:
  • Initial dosing: 300–600 mg testosterone enanthate/week (IM) or 50–100 mg/day transdermal.
  • Monitoring: Serum testosterone (target: 400–700 ng/dL), PSA (prostate-specific antigen), and hematocrit (risk of polycythemia).
  • Combination therapy: TRT + growth hormone (GH) or dhea may synergize in cachexia (e.g., 2–4 IU GH/day in COPD patients).
    • Caution: Anabolic steroids carry risks of cardiovascular strain, liver toxicity, and psychological effects. Short-term, supervised use in clinical settings (e.g., oxandrolone for HIV wasting) is preferred over long-term abuse.
    Myostatin Inhibitors and Emerging Biologics
    Myostatin (GDF-8) suppresses muscle growth by inhibiting myogenic differentiation. Inhibitors like ACE-011 (luspatercept) and bimagrumab have shown 2–5% muscle mass increases in phase II trials for Duchenne muscular dystrophy (DMD) and cancer cachexia (Egan et al., 2021). Mechanisms include:
  • Antibody-mediated neutralization: Monoclonal antibodies (e.g., REGN1033) bind myostatin, reducing its inhibitory effects.
  • Soluble receptor traps: ACE-011 acts as a decoy receptor for activin/myostatin, promoting satellite cell activation.
  • Limitations: Off-target effects (e.g., bone marrow suppression with bimagrumab) and high costs (~$200,000/year) restrict widespread use.

    • Selective Androgen Receptor Modulators (SARMs)
    SARMs (e.g., enobosarm [GTx-024]) bind androgen receptors with tissue selectivity, sparing prostate and liver toxicity. Phase III trials in postmenopausal women and elderly men reported 1–2% muscle mass gains with 3–6 mg/day enobosarm over 3 months (Dalton et al., 2019). Advantages include:

  • Reduced androgenic side effects: No significant virilization or hepatic toxicity at therapeutic doses.
  • Combination potential: Synergizes with resistance training (e.g., 5% greater strength gains vs. placebo + RT).
  • Regulatory hurdles: FDA approval pending; current use is investigational.

    • Nutritional Therapy for Muscle Preservation

    Nutrition is a non-negotiable component of muscle-wasting interventions, as protein synthesis and energy availability directly influence anabolic resistance. Optimal strategies integrate protein timing, caloric balance, and targeted supplements to counteract catabolism.

    Protein Timing and Distribution
    Protein intake must align with muscle protein synthesis (MPS) kinetics, which peak at ~0.4–0.5 g/kg/meal and decline after 3–4 hours. Key principles include:

  • Frequency: 4–5 meals/day with 20–40 g protein per feeding maximizes MPS in elderly individuals (Morton et al., 2018).
  • Leucine content: 2–3 g leucine per meal (found in whey, casein, or soy) triggers MPS independently of total protein.
  • Case

    • Case Studies and Real-World Applications in Muscle Wasting

    Muscle wasting, or sarcopenia, presents distinct clinical challenges across different patient populations, requiring tailored diagnostic and therapeutic approaches. Real-world applications of muscle wasting research often involve complex patient histories, where physiological declines intersect with chronic diseases, aging, or systemic conditions. Case studies provide critical insights into disease progression, treatment efficacy, and adaptive strategies, while visualizing observable changes in patients helps clinicians and caregivers recognize early signs of functional decline. This section examines a hypothetical case of cancer-related muscle wasting, describes physical manifestations in elderly patients, and outlines evidence-based adaptive strategies for severe muscle wasting.
    A 62-year-old male patient with stage IV non-small cell lung cancer (NSCLC) presents with progressive unintentional weight loss (12% over 6 months), generalized muscle weakness, and fatigue. Initial diagnostic findings include:

    - Body Composition Analysis (DXA Scan):

  • Skeletal Muscle Mass Index (SMI): 6.8 kg/m² (normal: ≥7.0 kg/m² for males).
  • Fat-Free Mass Loss: 20% below baseline, with visceral fat depletion despite stable body weight.
  • Handgrip Strength: 18 kg (reference: ≥30 kg for males aged 60–69).

    • - Laboratory Results:

  • Elevated Inflammatory Markers: CRP (25 mg/L, normal <5), IL-6 (40 pg/mL, normal <7).
  • Hypoalbuminemia: 3.2 g/dL (normal: 3.5–5.0).
  • Anemia: Hemoglobin 10.5 g/dL (normal: 13.5–17.5).
  • Normal Thyroid Function and Vitamin D Levels (25-OH: 20 ng/mL, normal ≥30).

    • - Functional Assessment:

  • 6-Minute Walk Test (6MWT): 250 meters (predicted: 500+ meters).
  • Short Physical Performance Battery (SPPB): Score of 4/12 (severe mobility impairment).
  • Patient-Reported Outcomes: ECOG Performance Status = 3 (capable of only limited self-care).

    • Treatment Progression:
    1. Nutritional Intervention (First 4 Weeks):

  • High-Protein Diet (1.2–1.5 g/kg ideal body weight/day) with omega-3 fatty acids (eicosapentaenoic acid, EPA).
  • Oral Nutritional Supplements (ONS): 2,000 kcal/day, enriched with arginine, glutamine, and HMB.
  • Enteral Nutrition via PEG Tube: Initiated due to dysphagia and poor oral intake.
  • Outcome: Stabilization of weight loss but no significant muscle regrowth (SMI remains 6.7 kg/m²).

    • 2. Pharmacological Therapy (Weeks 5–12):

  • Anabolic Agents: Testosterone replacement (transdermal gel, 50 mg/day) + selective androgen receptor modulator (SARM) anamorelin (100 mg/day).
  • Anti-Inflammatory: Low-dose prednisone (5 mg/day) for catabolic suppression.
  • Outcome: Handgrip strength improved to 22 kg, 6MWT increased to 300 meters, but fatigue persisted.

    • 3. Multidisciplinary Rehabilitation (Weeks 13–24):

  • Progressive Resistance Training (PRT): Supervised sessions 3x/week (focus on lower limbs and core).
  • Neuromuscular Electrical Stimulation (NMES): Applied to quadriceps (4x/week).
  • Physical Therapy Modifications: Use of recumbent bike for low-impact cardio.
  • Outcome: SMI increased to 7.1 kg/m², 6MWT reached 400 meters, and ECOG status improved to 2.

    • Final Outcome (6-Month Follow-Up):

  • Stabilized muscle mass but no complete reversal of cachexia.
  • Improved quality of life (reduced fatigue, better mobility).
  • Palliative Care Integration: Focus shifted to symptom management (pain, dyspnea) due to disease progression.
  • Key Lesson: Early nutritional and anabolic intervention delayed functional decline, but cancer progression remained the primary driver of muscle loss.

    • Visual and Functional Progression of Muscle Wasting in Elderly Patients

    Muscle wasting in elderly patients (sarcopenia) follows a predictable pattern of physical and functional decline, often accelerated by comorbidities such as diabetes, heart failure, or chronic kidney disease. Below is a descriptive progression based on observable changes:

    - Early-Stage (Mild Sarcopenia):

  • Physical Appearance:
  • Reduced muscle girth in limbs (e.g., arms appear "stringy" despite normal body weight).
  • Increased subcutaneous fat (paradoxical obesity) while lean mass diminishes.
  • Postural changes: Slightly rounded shoulders, kyphosis due to weakened paraspinal muscles.
  • Functional Decline:
  • Slower gait speed (<0.8 m/s, indicative of pre-frailty).
  • Difficulty rising from a chair without using arms.
  • Reduced balance: Increased risk of falls (e.g., inability to stand on one leg for >10 seconds).

    • - Moderate-Stage (Established Sarcopenia):

  • Physical Appearance:
  • Visible muscle atrophy in quadriceps, calves, and deltoids (e.g., "hollowed" appearance under skin).
  • Prominent bony landmarks (e.g., ribs, clavicles, iliac crests) due to fat redistribution.
  • Skinfold thinning with wrinkling from reduced collagen synthesis.
  • Functional Decline:
  • Dependence on assistive devices (cane, walker) for ambulation.
  • Inability to climb stairs without extreme fatigue.
  • Reduced hand dexterity (e.g., difficulty buttoning shirts, opening jars).

    • - Severe-Stage (Advanced Sarcopenia/Frailty):

  • Physical Appearance:
  • Extreme muscle wasting with visible tendons and bones in limbs.
  • Loss of subcutaneous fat leading to a "cachectic" appearance (despite possible obesity).
  • Edema in lower limbs due to reduced muscle pump function and immobility.
  • Functional Decline:
  • Bedbound or wheelchair-dependent with minimal independent movement.
  • Loss of speech clarity (due to tongue and throat muscle atrophy).
  • Pressure ulcers from prolonged immobility and poor nutritional status.

    • Key Observational Cues for Clinicians:

  • Gait Analysis: Shuffling steps, wide base of support, and reduced arm swing.
  • Hand Assessment: Thinning of thenar eminence (loss of grip strength).
  • Chair Stand Test: Unable to complete 5 stands without rest (indicates severe sarcopenia).

    • Adaptive Strategies for Patients with Severe Muscle Wasting

    Patients with advanced muscle wasting require multidisciplinary adaptive strategies to maintain functionality, mobility, and quality of life. These strategies focus on compensating for lost muscle strength, preventing secondary complications, and optimizing independence. Below is a structured approach categorized by intervention type:

    Assistive Devices and Mobility Aids
    Severe muscle wasting often necessitates external support to offset weakness. Proper selection reduces fall risk and preserves residual muscle function.

  • Wheelchairs and Mobility Scooters:
  • Power-assisted wheelchairs for patients with upper-body strength but lower-limb paralysis.
  • Reclining chairs to reduce pressure ulcers and improve breathing mechanics.
  • Ambulation Aids:
  • Forearm crutches or walkers for patients with partial weight-bearing capacity.
  • Hip guides or canes with seats for fatigue management during transfers.
  • Seating and Positioning Systems:
  • Custom orthotic cushions (e.g., roho cushions) to prevent decubitus ulcers.
  • Adjustable bed frames with trapeze bars for independent repositioning.

    • Modified Physical Therapy and Exercise Interventions
    Traditional exercise programs must be adapted for safety and efficacy in severely wasted patients.

  • Low-Impact Resistance Training:
  • Isokinetic machines (e.g., Biodex System 4

    Muscle wasting is not merely a consequence of aging or disease but a dynamic and reversible process when approached with a multidisciplinary strategy. From identifying high-risk populations—such as elderly individuals, cancer patients, or those with prolonged immobility—to leveraging advanced diagnostic tools like DEXA scans and biomarker analysis, early detection remains pivotal. Interventions must integrate resistance training, optimized nutrition, and, where applicable, pharmacological support to restore muscle protein synthesis and mitigate degradation. As research advances, the integration of personalized medicine—tailoring therapies to individual biochemical profiles—holds promise for reversing muscle loss and improving functional outcomes. Ultimately, addressing muscle wasting demands collaboration across healthcare disciplines to translate scientific insights into actionable clinical care.

    • FAQ

    What is muscle wasting disease and how does it affect the body?

    Muscle wasting disease refers to the progressive loss of muscle mass and strength, often caused by conditions like muscular dystrophy, cachexia, or sarcopenia. It occurs when muscles break down faster than they repair, leading to weakness, fatigue, and impaired mobility. Underlying causes can include genetic disorders, chronic illnesses (e.g., cancer, HIV), aging, or malnutrition.

    What is muscle wasting called in medical terms?

    Muscle wasting is medically called sarcopenia when related to aging, cachexia when linked to severe illness (e.g., cancer), or muscle atrophy in general terms. Specific diseases like muscular dystrophy or myopathy also involve muscle wasting but have distinct diagnostic criteria.

    What is the difference between muscle wasting and muscle atrophy?

    Muscle wasting is the broader term for the loss of muscle mass and function, often due to disuse, disease, or aging. Muscle atrophy specifically refers to the shrinkage of muscle fibers at the cellular level, which can occur locally (e.g., from a cast) or systemically (e.g., in starvation or illness). Atrophy is a mechanism that contributes to wasting, but wasting encompasses additional factors like inflammation or metabolic changes.

    What causes muscle wasting in dogs and how is it treated?

    Muscle wasting in dogs (canine sarcopenia or cachexia) is often caused by chronic illnesses (e.g., kidney disease, cancer), malnutrition, endocrine disorders (like hypothyroidism), or aging. Treatment focuses on addressing the underlying condition, high-protein diets, supplements (e.g., omega-3s, creatine), and controlled exercise to preserve muscle function.

    What is muscle wasting disease called in medical terminology?

    Muscle wasting disease can be referred to as sarcopenia (age-related), cachexia (disease-associated, e.g., cancer), or myopathy if caused by muscle tissue disorders. Terms like muscular dystrophy or amyotrophic lateral sclerosis (ALS) describe specific genetic or neurodegenerative conditions involving muscle degradation.

    What are the signs of muscle wasting in cats and what might cause it?

    Signs of muscle wasting in cats include visible weight loss, a "hollow" appearance behind the shoulders, weakness, or difficulty jumping. Common causes are chronic kidney disease, hyperthyroidism, cancer, malnutrition, or parasitic infections. Diagnosis typically involves blood tests, imaging, and treating the underlying condition with diet adjustments or medication.