Identifying the challenges for successful pharmacotherapeutic management of sarcopenia

KEYWORDS:

• Aging
• dystrophin
• exercise
• healthspan
• hormone
• longevity
• muscle wasting
• muscle weakness
• metabolism
• neuromuscular
• nutrition
• physiology
• sarcopenia
• strength

1. Introduction

Skeletal muscle is essential for life and maintaining muscle health is especially important for the quality of life that contributes to healthy longevity. Muscle contraction is responsible for inflating the lungs; for chewing and swallowing food; for maintaining posture, and providing the capacity to walk, run, cycle or swim, as well as perform the tasks of everyday living essential for functional independence, including the ability to feed oneself and maintain personal hygiene. Skeletal muscle is also an organ of metabolism, with contracting muscles releasing factors that circulate and communicate with other organs that help maintain the integration of the body’s systems for homeostasis and providing the capacity to respond and adapt to physiological challenges.

The potential mechanisms contributing to age-related changes in skeletal muscle mass and function (sarcopenia) have been described in detail many times elsewhere [1–3]. Despite continuing debate and a frustrating lack of consensus among different groups and agencies regarding specific definitions of sarcopenia, there is general agreement that with advancing age, muscles tend to become smaller and weaker, and this compromises the capacity to perform daily tasks and maintain independence. The loss of muscle strength, in absolute and relative terms (i.e. in proportion to their size and mass), indicates these functional deficits have underlying origins at multiple sites linked with excitation-contraction (E-C) coupling, Ca²⁺-handling, and force transmission. Fast (twitch) muscle fibers tend to be more susceptible to age-related deficits than slow (twitch) muscle fibers and this can contribute to an overall slowing of contraction that renders movements slower and less precise and places frail elders at considerable risk for falls and subsequent fractures. While research investment in sarcopenia by large pharma has waxed and waned over the last two decades, interest in the pursuit of longevity (rather than sarcopenia per se) and identifying ways that promote lifespan, continues to gain attention and financial investment. Ideally, these well-funded ventures will undertake and fund research dedicated to healthspan and therefore seek to better understand the mechanisms underlying muscle dysfunction with advancing age.

The fundamental biological questions that inform development of therapies for sarcopenia are whether the effects of aging on skeletal muscle are: 1) inevitable; 2) immutable; or 3) able to be attenuated. There are differing opinions about the answers to these questions, particularly whether the effects are inevitable or immutable, but a wealth of evidence shows they can be attenuated, at least to some extent, through exercise and nutrition. Preserving muscle function is key to maintaining functional independence and promoting healthspan. Many hundreds of studies have shown that strength or resistance training can attenuate the effects of aging on muscle health, especially when combined with a nutrition plan that addresses the protein needs that promote the retention and growth of skeletal muscle. These studies have shown that even nonagenarians living in nursing homes can respond favorably to structured programs of resistance exercise, with respect to improvements in skeletal muscle function that enhance quality of life, indicating that muscle remains responsive to exercise challenges even in the very elderly. Optimizing these interventions for specific groups of older adults continues to receive considerable attention [4].

Despite the obvious benefits of exercise in promoting healthy aging, the reality is that physical activity (and nutrition) alone cannot stop the progressive decline in muscle health. This is evident from the many studies of elite Masters-level athletes, who train and compete across their lifespan. Although marveling at their athletic prowess and achievement even in the twilight of their careers, the physiological reality is that even the best athletes are unable to perform as well as they did when they were younger. Whether in sprint or endurance running, weightlifting or in different field events, athletic performance declines with advancing age, even in genetically gifted athletes who maintain optimal exercise and nutrition programs throughout their long careers. Of course, there is no question that these activities contribute to better long-term health, functional independence, and quality of life, but the data are clear that exercise and nutrition alone are insufficient and that the effects of aging on muscle health are inevitable.

This leaves the question of whether the effects of aging on skeletal muscle are immutable. By extension, are the changes reversible? The ability to alter the course or trajectory of these age-related changes and promote healthspan, beyond exercise and nutrition interventions, depends on better understanding the mechanisms responsible for the deficits in muscle structure, function, and metabolism, and identifying pharmacotherapeutic targets. Contributing mechanisms include (but are not limited to) changes in circulating muscle anabolic hormones and growth factors that maintain the balance between protein synthesis and protein degradation to maintain muscle fiber size; whether there is patent electrical contact between stimulating nerves and contracting muscle fibers; whether the local muscle or systemic environment is plagued by inflammation and/or oxidative stress; whether blood flow can be maintained to supply nutrients to contracting muscles; and age-related impairments in muscle regenerative capacity, attributed to some of the mechanisms already mentioned, and potentially to changes in the inherent properties of the muscle’s resident population of satellite cells or muscle stem cells [5,6]. Not only do these potential contributing mechanisms identify as potential targets for pharmacotherapies, but the efficacy of any treatment could be compromised by not addressing one or more of these factors. It is important to consider these as some of the potential challenges for the pharmacotherapeutic management of sarcopenia.

2. Mechanistic challenges

2.1. Inflammation and metabolism

Chronic, low-grade, local, or systemic inflammation has been implicated in the development and severity of age-related muscle dysfunction [7] and more recently in the physical dysfunction associated with acute coronavirus disease (COVID)-19 and those patients exhibiting persistent symptoms that do not resolve over many months, linked with the post-acute sequelae of COVID-19 or Long COVID [8]. The efficacy of exercise, nutrition, or pharmacologic interventions for sarcopenia, can all be compromised by inflammation, which interferes with normal anabolic signaling and metabolism [9]. For example, leucine, the branched-chain amino acid that most effectively stimulates muscle protein synthesis in healthy muscle by directly modulating activity of the mechanistic target of rapamycin complex 1 (mTORC1) to initiate mRNA translation, cannot stimulate protein synthesis in models of acute inflammation. Strategies to overcome this form of ‘anabolic resistance’ may be needed to enhance the efficacy of other pharmacotherapies for sarcopenia [10].

In addition to non-steroidal anti-inflammatory drugs (NSAIDs) to target inflammatory cytokine signaling, mTOR inhibitors, renin–angiotensin system modulators, and metformin, are being investigated to address age-related metabolic dysfunction with relevance to sarcopenia [11]. Mimicking the benefits of exercise has therapeutic potential for sarcopenia and many other muscle disorders, especially when patients are unable (or limited in their capacity) to perform any physical activity. Attention has focussed on targeting AMP-activated protein kinase (AMPK) signaling to elicit (endurance-like) benefits to skeletal muscle, with several compounds being repurposed as ‘exercise mimetics’ [12]. Mimicking the benefits of resistance training (and possibly co-treating with more selective AMPK activators), must also be considered if these approaches are to be effective pharmacotherapies for sarcopenia. Senolytic drugs (‘senotherapeutics’) that target senescent cells or inhibit the senescence-associated secretory phenotype, have received considerable attention for their potential application to treat age-related diseases [13].

2.2. Hormonal insufficiency

Aging is associated with the decreased production and circulating levels of hormones and growth factors, like growth hormone, testosterone, and insulin-like growth factor-I, which exert anabolic effects on skeletal muscle to preserve muscle fiber size. Hormone replacement strategies have long been advocated as an approach to mitigate age-related deficits in physiology and if specific safe and effective approaches could be identified for broad application, these could also be considered as part of a suite of pharmacotherapies for sarcopenia [14].

2.3. Integrity of the neuromuscular junction

To maintain normal muscle function there needs to be a patent connection between the stimulating nerve and muscle, including pre- and post-synaptic (endplate) structures. Age-related changes in the structure and function at the neuromuscular junction (NMJ) have been implicated in the loss of muscle function [15]. If the integrity of the NMJ is compromised, this could render muscle fibers partially or fully denervated and susceptible to rapid atrophy [16], so preservation of these structures will also influence the efficacy of pharmacotherapies for sarcopenia.

2.4. Preservation of the motor unit pool

Although extensive motor unit remodeling is more likely to occur only in the most severe cases of sarcopenia, it remains a potential contributing mechanism in the loss of muscle function with advancing age [17]. Preservation of fast motor units would contribute to the maintenance of muscle mass and strength, but extensive remodeling through loss of fast muscle fibers and reinnervation could alter muscle phenotype and thus the response to pharmacotherapies [18].

A potential intervention strategy for sarcopenia could be the use of troponin activators of fast skeletal muscle [19] that work to enhance the force-producing capacity or Ca²⁺-sensitivity of type II fibers to improve muscular strength and physical performance. These studies have shown some promise for troponin activators to treat muscle weakness in neuromuscular diseases [20] but they require closer evaluation in the context of addressing the functional consequences of sarcopenia.

2.5. Stability of the dystrophin-glycoprotein complex and related membrane-associated proteins

In addition to the well-reported roles of the dystrophin-glycoprotein complex (DGC) in the maintenance of muscle structure and force transmission, evidence is mounting for its important anabolic and vascular-signaling roles [21]. Loss of DGC integrity and compromised force transmission has been reported in muscles of aged rats, well before substantial changes in muscle mass [22]. Loss of membrane-associated proteins not only disrupts the transmission of sarcomere-generated forces across those structures and externally to facilitate movement, but their absence or mislocalization could compromise the anabolic signaling required for maintenance of muscle mass or the response to pharmacotherapies, especially growth-promoting agents. Strategies to address age-related muscle wasting and weakness need to consider the importance of preserving membrane integrity and the scaffold of proteins that serve functions beyond the transmission of contractile forces.

3. Other challenges

In addition to the biological mechanisms contributing to age-related muscle wasting and weakness, other challenges that affect the implementation and efficacy of pharmacotherapies need to be considered. Even when a mechanistic target has been identified and interventions formulated for potential clinical application, there are remaining challenges to overcome for their successful translation.

3.1. Risk:benefit

The ability to successfully modify muscle mass (and ideally function) through pharmacological approaches, often comes at some other physiological cost; typically, off-target effects that limit or preclude widespread clinical application. For example, anabolic agents, such as testosterone (and its derivatives), growth hormone, β₂-adrenoceptor agonists, and many others, can exert powerful muscle growth-promoting effects, but these potential benefits can come at the risk of off-target effects, including cardiac/cardiovascular, cancers, or other organ complications, depending on the dose, route of administration, frequency, and duration of treatment [23,24]. These effects may be offset through consideration of co-treatments that address off-target effects or modifying the duration of treatments. Although off-target complications could be minimized through muscle-specific interventions rather than systemic administration, whether this is a realistic scenario depends on which muscles or muscle groups are being targeted and whether sarcopenia is better addressed at a whole-body level.

In the case of testosterone, co-administration with finasteride, a type II 5α-reductase inhibitor, increased muscle strength and bone mineral density without causing prostate enlargement [25]. In non-hypogonadal healthy 65–75-year-old men, short-term (six week) administration of testosterone in addition to resistance exercise training, enhanced muscle mass, and performance, compared to men who did the same exercise but received a placebo treatment [26]. No adverse effects were reported with short-term treatment. The authors suggested that older women might also benefit given the similar link between declining testosterone and muscle aging in women, but reiterated that older adults receiving testosterone therapy should be carefully monitored because of potential health risks [26]. Senolytics targeting senescent cells hold much promise for their therapeutic benefits, but side effects have been identified in some studies, including potential mitochondrial impairments [27] and potential cardiotoxity [28].

Of course, these risk: benefit scenarios apply across all fields of biomedicine, but are especially relevant in the context of aging and healthy longevity where the long-term preservation of muscle function is essential for maintaining functional independence and quality of life. The Internet and different social media platforms are replete with scientific and not-so-scientific discussions regarding pharmacological therapies and their use in athletics, bodybuilding, and longevity pursuits. These forums highlight the widespread (and often unregulated) use of pharmacologics for different purposes and the potential for these practices to cause more health problems rather than identifying safe and effective strategies for clinical application.

3.2. Patient characteristics

The relative efficacy of pharmacotherapies for sarcopenia may also depend on the physiological characteristics of the intended patient population. Some may respond more favorably to specific treatments than others, perhaps dependent on their relative musculature (mass and quality of muscle available and responsive to treatment), and their ability to tolerate short- or long-term interventions. Nutritional approaches may be limited by the patient’s ability to easily chew and swallow food, or their relative muscle sensitivity for amino acid feeding to support protein turnover [29]. The efficacy of nutritional and pharmacological interventions for sarcopenia could also be enhanced if administered in conjunction with an appropriate exercise program, especially one promoting muscle health through resistance (strength) training. While there are many studies reporting the benefits of resistance training for older adults, the most effective exercises to preserve muscle function are typically those dynamic, multi-joint movements performed at a higher intensity. Realistically, these exercises can be very challenging for fit, young people, let alone for older adults who are likely to be more limited in their exercise options. For tackling sarcopenia, exercise programs should ideally be tailored to individual needs and toward realistic goals that promote better health and quality of life, and help reduce the need for hospitalization and institutionalization.

4. Therapeutic window of opportunity for sarcopenia

Another consideration influencing the efficacy of pharmacotherapies for sarcopenia is the timing of intervention(s). Given that the age-related deterioration in muscle health is typically slow and progressive, is it better to intervene only when functional deficits become evident, or should preventive pharmacotherapeutics be considered that slow the rate of decline and attenuate the loss of muscle health? Since exercise and nutrition strategies are the mainstay of existing preventive lifestyle approaches for sarcopenia, consideration of pharmacotherapies with benefits synergistic to lifestyle interventions will depend on their relative risk: benefit profile and on the timing and frequency of administration. Interventions that can preserve or attenuate the loss of function are likely to be more realistic and achievable than interventions hoping to reverse the loss of muscle mass and function. This concept of a relative therapeutic window of opportunity is especially relevant in the context of treating neuromuscular diseases (like severe muscular dystrophies) but the concept is similarly important in considerations for sarcopenia, given the neuromuscular deficits that can occur during aging.

5. Expert opinion

Although considerable work is being undertaken to better understand the mechanisms responsible for age-related muscle wasting and weakness and to develop interventions that can counteract these effects, significant physiological challenges must be overcome to optimize their efficacy for sarcopenia. These often overlooked mechanistic challenges include the need to overcome metabolic alterations caused by deficits in circulating anabolic hormones and growth factors, chronic (local and/or systemic) elevations in inflammatory markers, and changes in structural proteins that alter cellular stability and disrupt anabolic signaling, E-C coupling, and force transmission. Each of these challenges represents a significant area of study and addressing them also has relevance for many muscle-related disorders in addition to sarcopenia, including neuromuscular diseases and a range of muscle wasting conditions, such as cancer cachexia, chronic heart failure, chronic kidney disease, peripheral arterial disease, metabolic diseases, critical care illness, and the consequences of severe burn injury. The efficacy of nutrition, exercise, or pharmacologic interventions for sarcopenia will be compromised unless these challenges are addressed; an analogy being the futility of trying to fill a bucket with water when it contains many large holes. Aside from these mechanistic challenges, other barriers include the risk: benefit for different interventions and the relative therapeutic window of opportunity for effectively addressing age-related physiological deficits. These challenges should be considered when developing pharmacotherapies for sarcopenia in order for them to meet clinically relevant outcomes related to functional independence and improved healthspan.

Declaration of Interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.