madman
Super Moderator
Getting deep here, enjoyed this one!
Abstract
Sarcopenia is a skeletal muscle disorder characterized by a progressive and generalized decline in muscle mass and function. Although it is mostly known as an age-related disorder, it can also occur secondary to systemic diseases such as malignancy or organ failure. It has demonstrated a significant relationship with adverse outcomes, e.g., falls, disabilities, and even mortality. Several breakthroughs have been made to find a pharmaceutical therapy for sarcopenia over the years, and some have come up with promising findings. Yet still no drug has been approved for its treatment. The key factor that makes finding effective pharmacotherapy so challenging is the general paradigm of standalone/single diseases, traditionally adopted in medicine. Today, it is well known that sarcopenia is a complex disorder caused by multiple factors, e.g., imbalance in protein turnover, satellite cell and mitochondrial dysfunction, hormonal changes, low-grade inflammation, senescence, anorexia of aging, and behavioral factors such as low physical activity. Therefore, pharmaceuticals, either alone or combined, that exhibit multiple actions on these factors simultaneously will likely be the drug of choice to manage sarcopenia. Among various drug options explored throughout the years, testosterone still has the most cumulated evidence regarding its effects on muscle health and its safety. A mas receptor agonist, BIO101, stands out as a recent promising pharmaceutical. In addition to the conventional strategies (i.e., nutritional support and physical exercise), therapeutics with multiple targets of action or a combination of multiple therapeutics with different targets/modes of action appear to promise greater benefit for the prevention and treatment of sarcopenia.
Introduction
*In this article, we aimed to detail the complex pathophysiological pathway of sarcopenia, thereby outlining the possible targets or pathways for effective treatment (s). We review the completed and/or ongoing trials for pharmacological treatments so far and present future directions of therapeutic options.
2 Pathophysiology of Sarcopenia
Sarcopenia is a complex multifactorial geriatric syndrome. The underlying etiological factors and pathways are not fully understood. Both intrinsic factors within the muscle (e.g., apoptosis or autophagy) and systemic factors (e.g., hormonal changes and inflammatory status) can lead to the development of structural and functional deterioration in muscle[17–19]. The etiological factors of sarcopenia are detailed below (Fig. 1).
2.1 Imbalance in Muscular Protein Turnover
2.1.1 Muscle Protein Synthesis
2.1.2 Muscular Breakdown
2.2 Impaired Neuromuscular İntegrity
2.3 Changes in the Satellite Cells
2.4 Mitochondrial Dysfunction
2.5 Inflammation
2.6 Hormonal Changes
2.7 Renin–Angiotensin System (RAS)
2.8 MicroRNAs (miRNAs)
2.9 Dysbiosis
2.10 Behavioral Factors
3 Current Treatment of Sarcopenia
The basic treatment of sarcopenia at present depends on nonpharmacological strategies, i.e., exercise, optimum energy(calorie), protein intake/protein supplementation, and optimum intake of vitamin D and essential micronutrients[13, 118–121]. Resistance training is accepted as the most effective way to improve muscle mass and functions [118]. Likewise, aerobic training is also known for its beneficial effect in not only improving muscle mass and functions but also endurance and cardiovascular well-being [119].
Adequate protein, calorie, and vitamin D intake is essential to maintain muscle health. To prevent muscle loss, the recommended daily protein intake for healthy older adults is 1.0–1.2 g/kg body weight (BW), for older individuals with acute or chronic diseases it is 1.2–1.5 g/kg BW, and for older individuals with critical illness or malnutrition it is up to2.0 g/kg BW [120]. Vitamin D replacement is especially recommended for individuals suffering its deficiency since it is reported to improve muscle functions, falls, and mortality in older people with deficiency [121, 122]. The benefit of vitamin D supplementation on muscle functions has been reported, particularly in older women with very low vitamin D levels (< 25 nmol/L or < 10 ng/mL) and without over-supplementation (< 1000 IU/day) [121, 123]. Omega-3 (n3-polyunsaturated fatty acids; n3-PUFA) supplementation was also reported to be beneficial for muscle mass and volume, with more evident effects with higher doses (> 2g/day) [124]. Omega-3 may positively affect muscle protein synthesis response to anabolic stimuli, alleviating age-related anabolic resistance. It also seems to improve muscle strength and physical performance, although the evidence is conflicting and comes from meta-analysis with high protocol heterogeneity [125]. Selenium, magnesium, and inorganic nitrate have also been studied as dietary intake or supplements in clinical studies and appear to have a potential association with muscle performance and physical activity in older adults, but the evidence is limited compared with omega-3 [13, 126]. Creatine intake during resistance training is also suggested to increase the ability to exercise at high intensities and enhance post-exercise recovery and adaptation in older adults [124]. Overall, healthier diets of higher quality across adulthood are linked not only to lower risks of noncommunicable diseases like diabetes or cancer but also to the preservation of muscle mass and function [127]
4 Pharmacological Therapy of Sarcopenia
4.1 Hormonal Therapies
4.1.1 Testosterone
In summary, testosterone is the therapeutic agent embodying the richest evidence for improving muscle mass and strength, while worrisome adverse effects like increased cardiovascular events and prostate cancer should be considered especially with supraphysiologic doses. The ideal treatment regimen (dosage, formulation, and duration) promising the optimum risk-benefit balance between effectiveness and adverse effects of testosterone for older adults with sarcopenia is still under investigation.
4.1.2 Selective Androgen Receptor Modulators (SARMs)
Overall, although they were developed as alternative anabolic agents to testosterone due to safety concerns, the effects of SARMs on muscle still need to be solidified with further evidence. Therefore, long-term follow-up trials are needed to demonstrate the long-term safety and efficacy of SARMs.
4.1.3 Dehydroepiandrosterone (DHEA)
The positive effect of DHEA on sarcopenia components is inconclusive and needs to be elucidated by large-scale randomized controlled trials.
4.1.4 Estrogen‑Based Treatments and Selective EstrogenReceptor Modulators (SERMs)
In summary, estrogen-based therapies are not recommended to prevent or treat sarcopenia, due to conflicting and insufficient benefits on muscle mass and functions and their potential risks.
Nonetheless, further research is necessary to determine the efficacy of SERMs in adults with sarcopenia, since the current evidence is insufficient to support its use in sarcopenia (Table 1).
4.1.5 GH/IGF‑1/Insulin and Drugs For Type 2 Diabetes Mellitus as Potential Pharmacological Treatments for Sarcopenia
GH
Although it may have anabolic effects on muscle mass, the benefits on muscle functions have not been demonstrated to date. Moreover, its side effect profile raises concerns about its use with sarcopenia indication.
IGF-1
In summary, further clinical studies are needed to make firm conclusions on whether IGF-1 could be a safe and effective therapeutic strategy for sarcopenia.
Insulin
Although it does not seem likely to be used for the treatment of sarcopenia in individuals without (due to the risk of hypoglycemia), insulin therapy in DM may be used to take advantage of its anabolic effect in muscles as well as hyperglycemia treatment. Nevertheless, it is clear that more work is needed to be more conclusive (Table 1).
Metformin
Although metformin exhibits multiple pleiotropic effects on sarcopenia pathogenesis, available evidence regarding its effects on muscle health is contradictory. Further studies are needed to elucidate its role in the treatment of sarcopenia and whether its potential benefits outweigh its risks, considering its adverse effects on appetite and body weight.
GLP-1RA
Whether or not it is indicated for sarcopenia in the future, the use of GLP-1RA will require close monitoring and ensuring adequate protein intake in older adults in order not to lose the muscle reserve they already have (Table 1).
SGLT-2i
In summary, more studies are needed to determine whether SGLT-2i is beneficial especially in sarcopenic obesity and sarcopenic individuals without Diabetes Mellitus (Table 1).
Thiazolidinediones
Although the limited data available show that the positive effects of thiazolidinediones on muscle are not satisfactory, it is obvious that more studies are needed to make a clear claim (Table 1).
4.1.6 Ghrelin and Ghrelin Receptor Agonists
Indeed, ghrelin mimetics attracts attention as a therapeutic group that can be useful especially in catabolic conditions such as cancer cachexia, due to the effects on increasing LBM and total body weight. However, their effects on muscle functions are questionable, and more clinical studies are needed on their long-term efficacy and safety.
4.2 Myostatin and Activin II Receptor İnhibitors
In summary, among myostatin and activin II receptor inhibitors, bimagrumab stands out as an important therapeutic candidate, especially for sarcopenic obesity. Precise targeting seems to be more helpful in the case of developing myostatin-related drugs to narrow the spectrum of side effects [260].
4.3 Therapeutics with Actions on RAS
Further studies are needed to better clarify the effects of the agents for the classical RAS pathway on skeletal muscle (Table 1).
BIO101 is now considered to have the potential to become the first drug approved for the treatment of sarcopenia.
4.4 mTOR Inhibitors
There are a limited number of clinical trials on the effect of rapamycin or other rapalogs on muscle health in the literature, with findings showing that there is still a long way to go to elucidate whether this pathway can be used in the treatment of sarcopenia (Table 1).
4.5 Miscellaneous Drugs
Espindolol (MT-102) (S-isomer of pindolol)
It is clear that further large-scale studies are needed. That said, espindolol has the potential for use in cancer cachexia (Table 1).
AST-120 (renamezin)
This study shows that AST-120 (renamezin) has the potential to improve sarcopenia in patients with CKD, but should be supported with further evidence (Table 1).
Fast skeletal muscle troponin activators (FSTA)
Future studies will reveal whether this potential novel drug group will be an effective and safe choice for sarcopenia. At present, there is no ongoing trial studying the effects of FSTA on sarcopenia (Table 1).
Elamipretide (SS-31, MTP-131, Bendavia)
Thus, elamipretideis considered a novel class of drugs with potential for the treatment of sarcopenia (Table 1).
Anti-TNF therapy
Further studies will reveal whether anti-TNF therapy will get approval for the treatment of sarcopenia in the coming years (Table 1).
5 Challenges in the Development of Drugs for Sarcopenia and Future Directions
6 Conclusion
There has been an enormous effort to find an effective pharmacotherapeutic solution for sarcopenia over the last decades, and research still continues with some promising agents being in the current pipeline. Despite various therapeutic interventions being explored in a timely manner over the last decades, the effective options available against sarcopenia to date are still restricted to nutritional and exercise interventions. Among the drug candidates for sarcopenia, testosterone has the most accumulated evidence of anabolic effects on skeletal muscle and its safe profile in physiological doses. Bimagrumab (BYM338) is a promising drug candidate for especially sarcopenic obesity, showing dual effects of an increase in LBM and a decrease in fat mass. Ghrelin receptor agonists and espindolol are other promising drug groups for cancer cachexia with their reported beneficial effects on muscle mass and body weight. However, large-scale studies are needed. BIO101 is one of the most promising drug candidates in recent years with its positive effect on muscle functions in sarcopenic patients, and the results of its phase III trial will be followed with interest. The one lesson learned from so many years of experience in pharmaceutical trials is probably not to overlook the complexity and the fact that more than one mechanistic pathway is involved in the pathophysiology of sarcopenia. The multiple pathophysiological pathways probably create a “sarcopenia spectrum,” ending with individuals having different etiological factors underlying the same outcome (namely sarcopenia), and seem to generate different treatment needs depending on which etiological factor(s) and pathway(s) are dominant.
Analogous to sarcopenia, one can consider T2DM since it has also complex multifactorial pathogenesis similar to sarcopenia. Although all patients with T2DM are classified under the same diagnostic name, some present with insulin resistance and obesity, while some others present with weight loss and insulin deficiency, and accordingly they need different treatment strategies (weight loss with insulin sensitizers for the former group and insulin treatment and sometimes weight gain for the latter group) [223]. In the case of sarcopenia, as a simple example, one can expect different treatment strategies in patients with sarcopenia along with cancer and malnutrition than those having sarcopenia and obesity (sarcopenic obesity). Therefore, revealing which pathway is dominant in sarcopenia on an individual basis with more advanced future diagnostic methods and creating tailored treatment strategies will most probably be a breakthrough in the future of pharmacotherapy in sarcopenia. Novel therapeutics with more than one potential target of action or an approach of combining pharmacotherapies with other existing modalities (such as nutritional support and exercise) or emerging modalities appear to be more effective in obtaining promising results from ongoing and future drug trials.
Abstract
Sarcopenia is a skeletal muscle disorder characterized by a progressive and generalized decline in muscle mass and function. Although it is mostly known as an age-related disorder, it can also occur secondary to systemic diseases such as malignancy or organ failure. It has demonstrated a significant relationship with adverse outcomes, e.g., falls, disabilities, and even mortality. Several breakthroughs have been made to find a pharmaceutical therapy for sarcopenia over the years, and some have come up with promising findings. Yet still no drug has been approved for its treatment. The key factor that makes finding effective pharmacotherapy so challenging is the general paradigm of standalone/single diseases, traditionally adopted in medicine. Today, it is well known that sarcopenia is a complex disorder caused by multiple factors, e.g., imbalance in protein turnover, satellite cell and mitochondrial dysfunction, hormonal changes, low-grade inflammation, senescence, anorexia of aging, and behavioral factors such as low physical activity. Therefore, pharmaceuticals, either alone or combined, that exhibit multiple actions on these factors simultaneously will likely be the drug of choice to manage sarcopenia. Among various drug options explored throughout the years, testosterone still has the most cumulated evidence regarding its effects on muscle health and its safety. A mas receptor agonist, BIO101, stands out as a recent promising pharmaceutical. In addition to the conventional strategies (i.e., nutritional support and physical exercise), therapeutics with multiple targets of action or a combination of multiple therapeutics with different targets/modes of action appear to promise greater benefit for the prevention and treatment of sarcopenia.
Introduction
*In this article, we aimed to detail the complex pathophysiological pathway of sarcopenia, thereby outlining the possible targets or pathways for effective treatment (s). We review the completed and/or ongoing trials for pharmacological treatments so far and present future directions of therapeutic options.
2 Pathophysiology of Sarcopenia
Sarcopenia is a complex multifactorial geriatric syndrome. The underlying etiological factors and pathways are not fully understood. Both intrinsic factors within the muscle (e.g., apoptosis or autophagy) and systemic factors (e.g., hormonal changes and inflammatory status) can lead to the development of structural and functional deterioration in muscle[17–19]. The etiological factors of sarcopenia are detailed below (Fig. 1).
2.1 Imbalance in Muscular Protein Turnover
2.1.1 Muscle Protein Synthesis
2.1.2 Muscular Breakdown
2.2 Impaired Neuromuscular İntegrity
2.3 Changes in the Satellite Cells
2.4 Mitochondrial Dysfunction
2.5 Inflammation
2.6 Hormonal Changes
2.7 Renin–Angiotensin System (RAS)
2.8 MicroRNAs (miRNAs)
2.9 Dysbiosis
2.10 Behavioral Factors
3 Current Treatment of Sarcopenia
The basic treatment of sarcopenia at present depends on nonpharmacological strategies, i.e., exercise, optimum energy(calorie), protein intake/protein supplementation, and optimum intake of vitamin D and essential micronutrients[13, 118–121]. Resistance training is accepted as the most effective way to improve muscle mass and functions [118]. Likewise, aerobic training is also known for its beneficial effect in not only improving muscle mass and functions but also endurance and cardiovascular well-being [119].
Adequate protein, calorie, and vitamin D intake is essential to maintain muscle health. To prevent muscle loss, the recommended daily protein intake for healthy older adults is 1.0–1.2 g/kg body weight (BW), for older individuals with acute or chronic diseases it is 1.2–1.5 g/kg BW, and for older individuals with critical illness or malnutrition it is up to2.0 g/kg BW [120]. Vitamin D replacement is especially recommended for individuals suffering its deficiency since it is reported to improve muscle functions, falls, and mortality in older people with deficiency [121, 122]. The benefit of vitamin D supplementation on muscle functions has been reported, particularly in older women with very low vitamin D levels (< 25 nmol/L or < 10 ng/mL) and without over-supplementation (< 1000 IU/day) [121, 123]. Omega-3 (n3-polyunsaturated fatty acids; n3-PUFA) supplementation was also reported to be beneficial for muscle mass and volume, with more evident effects with higher doses (> 2g/day) [124]. Omega-3 may positively affect muscle protein synthesis response to anabolic stimuli, alleviating age-related anabolic resistance. It also seems to improve muscle strength and physical performance, although the evidence is conflicting and comes from meta-analysis with high protocol heterogeneity [125]. Selenium, magnesium, and inorganic nitrate have also been studied as dietary intake or supplements in clinical studies and appear to have a potential association with muscle performance and physical activity in older adults, but the evidence is limited compared with omega-3 [13, 126]. Creatine intake during resistance training is also suggested to increase the ability to exercise at high intensities and enhance post-exercise recovery and adaptation in older adults [124]. Overall, healthier diets of higher quality across adulthood are linked not only to lower risks of noncommunicable diseases like diabetes or cancer but also to the preservation of muscle mass and function [127]
4 Pharmacological Therapy of Sarcopenia
4.1 Hormonal Therapies
4.1.1 Testosterone
In summary, testosterone is the therapeutic agent embodying the richest evidence for improving muscle mass and strength, while worrisome adverse effects like increased cardiovascular events and prostate cancer should be considered especially with supraphysiologic doses. The ideal treatment regimen (dosage, formulation, and duration) promising the optimum risk-benefit balance between effectiveness and adverse effects of testosterone for older adults with sarcopenia is still under investigation.
4.1.2 Selective Androgen Receptor Modulators (SARMs)
Overall, although they were developed as alternative anabolic agents to testosterone due to safety concerns, the effects of SARMs on muscle still need to be solidified with further evidence. Therefore, long-term follow-up trials are needed to demonstrate the long-term safety and efficacy of SARMs.
4.1.3 Dehydroepiandrosterone (DHEA)
The positive effect of DHEA on sarcopenia components is inconclusive and needs to be elucidated by large-scale randomized controlled trials.
4.1.4 Estrogen‑Based Treatments and Selective EstrogenReceptor Modulators (SERMs)
In summary, estrogen-based therapies are not recommended to prevent or treat sarcopenia, due to conflicting and insufficient benefits on muscle mass and functions and their potential risks.
Nonetheless, further research is necessary to determine the efficacy of SERMs in adults with sarcopenia, since the current evidence is insufficient to support its use in sarcopenia (Table 1).
4.1.5 GH/IGF‑1/Insulin and Drugs For Type 2 Diabetes Mellitus as Potential Pharmacological Treatments for Sarcopenia
GH
Although it may have anabolic effects on muscle mass, the benefits on muscle functions have not been demonstrated to date. Moreover, its side effect profile raises concerns about its use with sarcopenia indication.
IGF-1
In summary, further clinical studies are needed to make firm conclusions on whether IGF-1 could be a safe and effective therapeutic strategy for sarcopenia.
Insulin
Although it does not seem likely to be used for the treatment of sarcopenia in individuals without (due to the risk of hypoglycemia), insulin therapy in DM may be used to take advantage of its anabolic effect in muscles as well as hyperglycemia treatment. Nevertheless, it is clear that more work is needed to be more conclusive (Table 1).
Metformin
Although metformin exhibits multiple pleiotropic effects on sarcopenia pathogenesis, available evidence regarding its effects on muscle health is contradictory. Further studies are needed to elucidate its role in the treatment of sarcopenia and whether its potential benefits outweigh its risks, considering its adverse effects on appetite and body weight.
GLP-1RA
Whether or not it is indicated for sarcopenia in the future, the use of GLP-1RA will require close monitoring and ensuring adequate protein intake in older adults in order not to lose the muscle reserve they already have (Table 1).
SGLT-2i
In summary, more studies are needed to determine whether SGLT-2i is beneficial especially in sarcopenic obesity and sarcopenic individuals without Diabetes Mellitus (Table 1).
Thiazolidinediones
Although the limited data available show that the positive effects of thiazolidinediones on muscle are not satisfactory, it is obvious that more studies are needed to make a clear claim (Table 1).
4.1.6 Ghrelin and Ghrelin Receptor Agonists
Indeed, ghrelin mimetics attracts attention as a therapeutic group that can be useful especially in catabolic conditions such as cancer cachexia, due to the effects on increasing LBM and total body weight. However, their effects on muscle functions are questionable, and more clinical studies are needed on their long-term efficacy and safety.
4.2 Myostatin and Activin II Receptor İnhibitors
In summary, among myostatin and activin II receptor inhibitors, bimagrumab stands out as an important therapeutic candidate, especially for sarcopenic obesity. Precise targeting seems to be more helpful in the case of developing myostatin-related drugs to narrow the spectrum of side effects [260].
4.3 Therapeutics with Actions on RAS
Further studies are needed to better clarify the effects of the agents for the classical RAS pathway on skeletal muscle (Table 1).
BIO101 is now considered to have the potential to become the first drug approved for the treatment of sarcopenia.
4.4 mTOR Inhibitors
There are a limited number of clinical trials on the effect of rapamycin or other rapalogs on muscle health in the literature, with findings showing that there is still a long way to go to elucidate whether this pathway can be used in the treatment of sarcopenia (Table 1).
4.5 Miscellaneous Drugs
Espindolol (MT-102) (S-isomer of pindolol)
It is clear that further large-scale studies are needed. That said, espindolol has the potential for use in cancer cachexia (Table 1).
AST-120 (renamezin)
This study shows that AST-120 (renamezin) has the potential to improve sarcopenia in patients with CKD, but should be supported with further evidence (Table 1).
Fast skeletal muscle troponin activators (FSTA)
Future studies will reveal whether this potential novel drug group will be an effective and safe choice for sarcopenia. At present, there is no ongoing trial studying the effects of FSTA on sarcopenia (Table 1).
Elamipretide (SS-31, MTP-131, Bendavia)
Thus, elamipretideis considered a novel class of drugs with potential for the treatment of sarcopenia (Table 1).
Anti-TNF therapy
Further studies will reveal whether anti-TNF therapy will get approval for the treatment of sarcopenia in the coming years (Table 1).
5 Challenges in the Development of Drugs for Sarcopenia and Future Directions
6 Conclusion
There has been an enormous effort to find an effective pharmacotherapeutic solution for sarcopenia over the last decades, and research still continues with some promising agents being in the current pipeline. Despite various therapeutic interventions being explored in a timely manner over the last decades, the effective options available against sarcopenia to date are still restricted to nutritional and exercise interventions. Among the drug candidates for sarcopenia, testosterone has the most accumulated evidence of anabolic effects on skeletal muscle and its safe profile in physiological doses. Bimagrumab (BYM338) is a promising drug candidate for especially sarcopenic obesity, showing dual effects of an increase in LBM and a decrease in fat mass. Ghrelin receptor agonists and espindolol are other promising drug groups for cancer cachexia with their reported beneficial effects on muscle mass and body weight. However, large-scale studies are needed. BIO101 is one of the most promising drug candidates in recent years with its positive effect on muscle functions in sarcopenic patients, and the results of its phase III trial will be followed with interest. The one lesson learned from so many years of experience in pharmaceutical trials is probably not to overlook the complexity and the fact that more than one mechanistic pathway is involved in the pathophysiology of sarcopenia. The multiple pathophysiological pathways probably create a “sarcopenia spectrum,” ending with individuals having different etiological factors underlying the same outcome (namely sarcopenia), and seem to generate different treatment needs depending on which etiological factor(s) and pathway(s) are dominant.
Analogous to sarcopenia, one can consider T2DM since it has also complex multifactorial pathogenesis similar to sarcopenia. Although all patients with T2DM are classified under the same diagnostic name, some present with insulin resistance and obesity, while some others present with weight loss and insulin deficiency, and accordingly they need different treatment strategies (weight loss with insulin sensitizers for the former group and insulin treatment and sometimes weight gain for the latter group) [223]. In the case of sarcopenia, as a simple example, one can expect different treatment strategies in patients with sarcopenia along with cancer and malnutrition than those having sarcopenia and obesity (sarcopenic obesity). Therefore, revealing which pathway is dominant in sarcopenia on an individual basis with more advanced future diagnostic methods and creating tailored treatment strategies will most probably be a breakthrough in the future of pharmacotherapy in sarcopenia. Novel therapeutics with more than one potential target of action or an approach of combining pharmacotherapies with other existing modalities (such as nutritional support and exercise) or emerging modalities appear to be more effective in obtaining promising results from ongoing and future drug trials.
