The protein, GDF-15, is strongly associated with aging, poorly functioning mitochondria

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The protein, GDF-15, is strongly associated with aging, poorly functioning mitochondria. And aging mitochondria are strongly linked with fast biological aging.

The higher the level of GDF-15 in the blood, the more impaired the mitochondria tend to be. In other words, this is when our tiny power plants start to fall apart.

GDF-15 and Skeletal Muscle

Circulating levels of GDF-15 dramatically increase in a wide range of diseases without there being a singular predominant common denominator. A tight connection between GDF-15 and multiple pathogenic processes has been established and include chronic inflammation, tissue apoptosis, mitochondrial dysfunction, and oxidative stress.

Increased levels of GDF-15 have been observed in many human conditions in which muscle function is affected, as part of tissue stress responses. It remains uncertain whether GDF-15 induction is mostly of benefit or detrimental to muscle tissue recovery. For murine skeletal muscle, a direct catabolic effect on muscle cells has been observed in vivo [4,10] and in vitro [11].

GDF-15 appears to stimulate TGF-β-pathway-mediated fibrotic changes via downregulation of muscle-protective microRNAs. However, a positive effect of GDF-15 on myoblast proliferation has also been put forward, mediated by activation of regeneration-promoting programs in macrophages [12].

Under the control of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα), GDF-15 is co-expressed with well-known muscle regeneration-associated growth factors, and is expressed specifically in a subpopulation of macrophages involved in muscle repair.

Such contradictory activities of the same cytokine could be explained by beneficial effects mediated by cell-specific and timely expression that might activate very different mechanisms compared to the effects mediated by systemic upregulation. Indeed, chronically elevated circulating GDF-15 levels trigger adversary effects on growth and metabolism and mark a higher risk of all-cause mortality [13]. This review will give a general and concise roundup of the associations of GDF-15 with declining muscle health and evaluate its potential as a muscle disease biomarker and therapeutic target.

Age-Related Sarcopenia

From age 40 years onward, human skeletal muscle quantity and quality may decline progressively [14]. Such progressive and generalized loss of muscle mass and function is termed sarcopenia and represents a multifactorial process in which inadequate synthesis of muscle proteins plays a key role.

Muscle protein synthesis is regulated through Akt mammalian target of rapamycin (mTOR) activation, under the control of growth factors including testosterone and insulin-like growth factor 1 (IGF-1) and is stimulated by exercise [15]. During the aging process, anabolic hormone levels decline, which leads to decreased muscle protein synthesis and subsequent loss of muscle mass.

Sarcopenia compromises physical capacities of the growing population of people with an advanced age and is aggravated further by lifestyle factors including inactivity and poor nutrition [16]. Muscle impairment in the elderly results in progressive dependency and increases their risk of falls, fractures, and morbidities. Recognition of sarcopenia at an early stage allows taking measures to slow down progression and avoid excessive muscle loss. Interventions include resistance training, and nutraceuticals and drugs that stimulate muscle mass and strength building [17].

As a stress-induced cytokine, GDF-15 is considered a marker of biological age [18]. In aging, impaired mitochondrial function is a strongly associated mechanism, causing accumulation of reactive oxygen species and subsequent oxidative stress-induced tissue damage. While steady increases of circulating GDF-15 with advancing age may not be pathological, more pronounced elevation of GDF-15 exhibits an adversary effect on muscle mass, and associates with decreased muscle strength [19].

From mouse models, we know that increasing serum and muscle levels of GDF-15 in aging mice leads to reduced food intake, weight loss, and reduced skeletal muscle mass and function [20]. The muscle tissue itself actively contributes to the elevation of circulating GDF-15. Murine myotube cultures can be stimulated to produce GDF-15 by oxidative and endoplasmic reticulum stressors that mimic age-related stress [21].

While a firm and consistent association of GDF-15 with muscle catabolism comes forward in animal studies, it is less so in human studies. Some studies link sarcopenia, frailty, and reduced physical performance in older individuals with higher levels of circulating GDF-15 [20,22,23], other studies report gender-specificity [24] or fail to observe an association [25,26], or report that GDF-15 levels cannot predict sarcopenia [27]. Further studies are needed to confirm or refute if measuring circulating GDF-15 levels is helpful to recognize sarcopenia early in elderly individuals.

Disease-Related Sarcopenia

Muscle wasting associates with many human diseases and finds its origin in a multitude of mechanisms, which include oxidative stress, systemic inflammation, increased activity of the ubiquitin proteasome pathway, apoptosis, and/or an impaired regenerative potential of muscle [28], and is aggravated by disuse and malnutrition. In a multitude of human diseases, circulating GDF-15 levels are strongly increased, with levels negatively correlating with lean body and muscle mass [29] and positively correlating with patient fatigue scores [30]. The relationship between GDF-15 and pathologies that associate with sarcopenia will be discussed in this review.

Cardiovascular Disease

Heart disease accelerates the loss of muscle mass and severely compromises patients’ cardiorespiratory fitness and physical performance. Vice versa, sarcopenia may induce cardiovascular incidents [31]. Common contributing factors are physical inactivity, insulin resistance and malnutrition [32].

GDF-15 blood levels are extensively being explored as a cardiovascular disease marker indicative of metabolic health, and are reported to be increased in ischemia, heart failure, and hypertrophic and dilated cardiomyopathy [33,34], and in patients with type 2 diabetes at greater risk of heart failure [35]. GDF-15 is expressed in atherosclerotic lesion in arteries and seems actively involved in their formation and progression [36]. Circulating GDF-15 levels reflect renal dysfunction and muscle wasting in preoperative cardiovascular surgery patients [37].

For muscle health, preventive medication with statins, widely used to reduce cardiovascular risk, is a point of concern. These agents lower blood cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and, in addition, have beneficial immunomodulatory effects [38]. However, statins have also been linked to adverse effects of muscle damage and pain, and even rhabdomyolysis [39]. Although statin use is perceived as a probable risk for developing sarcopenia, the pros of cholesterol lowering drugs outbalance the possible risks. In addition, a study in heart failure patients observes, unexpectedly, that patients on statins develop sarcopenia less frequently than untreated patients [40]. Statins do not seem to influence GDF-15 levels, as is observed in diabetes type 2 patients on atorvastatin medication [41].

Chronic Inflammatory Diseases

In disorders characterized by chronic inflammation of lung and bowel, sarcopenia often co-exists and negatively impacts disease morbidities and mortality.
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide with ever increasing importance [42], and the prevalence of sarcopenia in patients is high [43]. Muscle wasting is accompanied by weakness and fatigue and a slow-to-fast shift in fiber type composition [44]. Increased levels of GDF-15 are firmly linked with COPD. The cytokine is involved in the buildup of pulmonary inflammation, and levels predict disease outcomes in patients [45,46]. Circulating GDF-15 levels negatively associate with skeletal muscle mass and strength in patients [47].

The allocated diagnostic performance of GDF-15 as a serum marker for sarcopenia in COPD is of 70% sensitivity and 90% specificity, with an area under the curve (AUC) of 0.83 [48].

The chronic inflammatory bowel diseases ulcerative colitis and Crohn’s disease (CD) exhibit similar symptoms of digestive dysfunction and inflammation. Disease symptoms may include weight loss, with an average of 1 in 10 patients suffering from sarcopenia [49]. Muscle wasting develops via a multifactorial process involving chronic inflammation, malabsorption of nutrients by the damaged intestine, disuse, and (glucocorticoid) therapy [50]. Serum levels of GDF-15 are increased in CD and are significantly higher in patients with low skeletal muscle mass index [51].

Cancer

Frailty due to progressive loss of body weight, fat, and muscle, termed cachexia, is very common in cancer patients and responsible for approximately 1 in 4 cancer deaths. In some cancers, the risk of developing cachexia is very high, for example as high as 70% in pancreatic cancers, while low incidence is observed in other cancers, for example in melanoma [52].

Underlying mechanisms are energy imbalance caused by reduced food intake, an inflammation-driven shift from anabolic to catabolic metabolic processes and impaired muscle protein translation [53,54]. In addition, chemotherapy may aggravate the loss of muscle mass and strength, compromising treatment dosage and continuation [55]. The important role GDF-15 plays in cancer is illustrated further by the association of gene variants of the cytokine with cancer risk [56], prognosis [57], and mortality [58].

The proposition of GDF-15 as a useful biomarker for cancer is long-standing [59]. GDF-15 is actively involved in cancer progression and invasion [60] and impacts the tumor immune environment via mitogen-activated kinase activities [29]. The cytokine is actively secreted by tumors, produced by the cancer cells themselves or by tumor-associated macrophages [61]. GDF-15 potentially has both protective and tumor-promoting activities, inhibiting tumor growth in the early stages while inversely promoting tumor cell proliferation at later stages via metabolic and immunomodulatory mechanisms [62]. Evidence accumulates of a positive association between GDF-15 levels and cancer-induced cachexia [4,29]. Animal models appoint GDF-15 with a direct metabolic effect via loss of appetite and subsequent weight loss [63]. In analogy with its emetic effect during pregnancy [64], GDF-15 is observed to also contribute to chemotherapy-induced nausea and vomiting [65].

Mitochondrial Myopathy

Inherited defects that cause mitochondrial dysfunction lead to impaired oxidative phosphorylation and subsequent energy-deficits. Mitochondrial diseases are notoriously heterogeneous with onset at any age and affecting any part of the body [66]. The genetic origin of defects is complex, as cellular factors required for mitochondrial functioning lie encoded in both the nuclear and the mitochondrial DNA, the latter being present in multiple copies and possibly in heteroplasmic state. This complexity of inheritance seriously complicates identification of the causal gene defect and prediction of disease severity [67]. Tissues with high energy demands are first victims, hence many mitochondrial defects associate with prominent muscular problems.

Due to a firm association of the cytokine with mitochondrial dysfunction, GDF-15 blood levels are now a well-established diagnostic biomarker for mitochondrial diseases [68,69,70,71,72]. Its performance is, however, varied and dependents on the nature of the genetic defect and the disease presentation. GDF-15 blood levels appear to be especially useful to diagnose early onset mitochondrial myopathy, and to identify mtDNA deletions and translation defects.

Affected muscle cells in muscle-manifesting mitochondrial disorders actively express and release GDF-15 [68,73], leading to increased circulating levels of the cytokine in patients. In a cohort of 48 patients diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome or Kearns-Sayre syndrome (KSS), serum GDF-15 had an impressive diagnostic sensitivity and specificity nearing 100% and AUC of 0.997 [69]. In a more diverse group of 16 patients with molecularly confirmed mitochondrial disorders, serum GDF-15 had a sensitivity of 70% and specificity of 90% and an AUC of 0.82. Highest levels of GDF-15 were present in the serum of patients with thymidine kinase 2 (TK2) defects, MELAS, defects in MT-TL1 encoding mitochondrial tRNA leucine, and patients with Pearson syndrome and KSS [70].

Autoimmune Myositis

Myositis of autoimmune origin is a heterogeneous group of rare disorders. Among its main subgroups recognized today are immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), sporadic inclusion body myositis (IBM), polymyositis (PM), and myositis as part of the anti-synthetase syndrome [74].

For further subtyping of patients into categories relevant to prognosis and therapeutic outcome, an expanding list of myositis-specific and myositis-associated auto-antibodies is available [75]. IBM is the most common form of autoimmune myositis in patients above the age of 50 years [76]. IBM patients develop degenerative changes of skeletal muscle comparable to those associated with aging however at an accelerated pace, which include mitochondrial dysfunction and disturbed mitophagy [77].

In analogy with mitochondrial myopathies, elevated levels of GDF-15 are detected in IBM patients [78,79]. Mitochondrial dysfunction is, however, a more general aspect of the disease mechanisms underlying autoimmune myositis, and is also noted in other subgroups of myositis patients. Abnormal mitochondrial activities have been observed in the atrophic perifascicular muscle fibers typically present in DM skeletal muscle biopsies [80].

Fitting with a more general involvement of mitochondrial dysfunction, increased GDF-15 levels are also indicative of DM, PM, and IMNM [81], however with lower sensitivities (70% versus 100%) and AUC (0.70 versus 0.92) in IMNM compared to IBM, respectively [82]. Another obvious mechanism responsible for the increased levels of GDF-15 in autoimmune myositis is related to the associated chronic inflammation and active regeneration of muscle fibers [78]. Although more studies are still needed, GDF-15 appears to be an attractive biomarker for further development, as it appears to be able to distinguish autoimmune myositis patients from those with hereditary disorders with secondary muscle inflammation [82].

SARS-CoV-2-Associated Myositis

Viruses can cause inflammation of skeletal muscle, with influenza- and entero-viruses most commonly reported [83]. Due to the ongoing coronavirus disease 2 (SARS-CoV-2) pandemic (COVID-19), SARS-CoV-2-associated viral myositis has, however, received much more attention recently. Myalgia, alongside respiratory manifestations and fever, features as a prominent symptom, and proximal muscle weakness is increasingly being reported in individual patients. The muscle involvement varies in severity from an asymptomatic elevation of creatine kinase (CK), a standard biomarker for muscle tissue damage, to severe rhabdomyolysis.

An increasing number of patients with myositis attributable to SARS-CoV-2 are being described [84]. Myositis is mediated through different underlying mechanisms, which include angiotensin-converting enzyme (ACE) receptor-mediated direct entry of the virus and triggering of innate and adaptive immune activation and T-cell clonal expansion, perpetuated by the continuous production of pro-inflammatory cytokines [85].

Mitochondrial stress is a key factor for the severity of COVID-19 disease and for triggering the devastating symptoms associated with the lethal cytokine storm [86]. Skeletal muscle-related symptoms are common in both acute and post-acute patients [87], with varied presentation in individual patients. A subset of patients develops autoimmune myositis.

SARS-CoV-2-induced classic DM has been reported, exhibiting the typical skin rashes and proximal muscle weakness [88]. Rarely, patients develop severe lung involvement in the presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies [89], strongly resembling anti-MDA5-positive autoimmune myositis [90]. Higher levels of GDF-15 are being reported in COVID-19 patients, most notably in those with poor outcome [91,92,93,94]. The association of GDF-15 expression with muscle manifestations is yet to be investigated.

reference link : https://www.mdpi.com/1422-0067/23/21/13180#

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