Muscle loss: does one size fit all? A comment on Bozzetti's paper

Dear Editor, Low muscle mass is common in several clinical conditions and is one of the hottest topics in clinical nutrition research. Until a few years ago, the term sarcopenia was used as a synonym for low muscle mass, and it is still used in the literature, especially to describe the muscle wasting presented in patients with cancer [1,2]. Sarcopenia is characterized by low skeletal muscle mass accompanied by motor function failure [3], leading to functional impairments. On the other hand, low muscle mass in clinical conditions refers to skeletal muscle mass as a systemic metabolic organ, which is associated with adverse clinical outcomes, Fig. 1[1,4]. Low muscle mass is a common criterion for diagnosing malnutrition, sarcopenia, sarcopenic obesity, and cachexia, and these conditions may overlap in hospitalized populations [2]. According to the Delphi Consensus from the Global Leadership Initiative in Sarcopenia (GLIS), sarcopenia is recognized as a generalized disease of skeletal muscle [5]. Its conceptual definition involves reductions in both muscle mass and muscle strength, and this definition is applied universally, regardless of the care setting, age, or condition.FIGURE 1: Consequences of muscle as a locomotor organ versus a metabolic organ, reflecting sarcopenia versus low muscle mass, respectively. The concept is fully explained in Cruz-Jentoft et al. [1].Dr Bozzetti presented an insightful paper highlighting differences between age-related and cancer-related sarcopenia [6]. The author discussed the distinct pathophysiology and therapeutic responses of muscle loss associated with aging compared to that caused by cancer. The paper also examined the impact of systemic cancer therapy on muscle loss. The first notable difference lies in the pathophysiology of age-related versus cancer-related muscle loss, leading to distinct skeletal muscle remodeling. Age-related muscle loss is well documented, with reductions in protein synthesis without changes in protein catabolism, and neuromuscular alterations playing significant roles. Consequently, motor unit loss, denervation, and reinnervation are prevalent, and muscle fibers become smaller due to reductions in protein turnover. In older adults over 60 years, the motor neuron pool and motor unit numbers can decrease by up to 50% [7]. These changes result in a muscle phenotype remodeling characterized by specific denervation, fiber loss, and atrophy, particularly in type II (fast-twitch or glycolytic) muscle fibers, which experience a reduction in both fiber number and cross-sectional area [7–10]. Another key mechanism in age-related muscle atrophy is the reduction of satellite cell numbers, which preferentially affects type II fibers, leading to more pronounced atrophy in glycolytic muscles [9]. This selective type II atrophy appears to be related to lipoxygenase-arachidonate 5-lipoxygenases (Alox-5), as inhibition of Alox-5 has been shown to preserve fast-twitch fibers and reduce muscle atrophy in aging muscles [9]. As with any age-related phenomenon, these changes vary widely among individuals, resulting in increased variability (standard deviation) of any given measure. Consequently, the extent of muscle atrophy differs broadly, and these changes are not universal. The histopathology of aging muscle has specific traits, such as fiber size heterogeneity and fiber type grouping, indicating that muscle atrophy in aging is distinct from atrophy in other clinical conditions [8]. Typically, myofiber size, evaluated by cross-sectional area, is considered the most important morphological characteristic of age-related atrophy. However, Soendenbroe et al. identified a new histopathological feature that can also be considered a hallmark of muscle aging: myofiber shape, assessed by a shape factor index (SFI) [11]. Age-induced neuromuscular disturbances and myofiber denervation may contribute to this myofiber deformation, particularly affecting type II myofibers. Consequently, this leads to a decrease in the type II/type I ratio. Myofiber shape can serve as a marker of muscle health in older adults, with a strong negative correlation to muscle mass and function measures. Notably, after 3–4 months of resistance training, older adults demonstrated improvements in type II myofiber shape and muscle size due to increased neuromuscular activity [11]. The underlying neural mechanisms of age-related muscle weakness have been recently reviewed [12]. The pathophysiology of cancer-related muscle atrophy remains under investigation. It appears that muscle depletion is initiated by a combination of tumor-derived catabolic factors and proinflammatory mediators, which may be exacerbated by weight loss due to cancer anorexia [6,9]. The skeletal muscle remodeling associated with cancer-related muscle loss is still controversial, based on limited clinical and preclinical studies. Bozzetti highlighted a key difference between age-related and cancer-related muscle loss: unlike aging, cancer also promotes a decline in type I fibers (slow twitch) to a greater extent than type II fibers, leading to an increase in type II/type I ratio, Fig. 2. This specific decline in oxidative fibers (mostly type 1 in humans) [13] may indicate that muscle disuse is an important contributor to muscle wasting in patients with cancer [7]. Type I fibers are also the most affected in disuse muscle atrophy after prolonged bed rest and in patients with type 2 diabetes mellitus [13,14]. However, findings regarding the decrease in the size of type 1 muscle fibers are controversial, as not all studies show a reduction [15]. Furthermore, a decrease in the proportion of type I fibers has only been observed in some animal studies, while the distribution between type I and type II fibers remains unchanged in the context of cancer cachexia [15].FIGURE 2: Selected differences between age-related and disease-related sarcopenia. Created with biorender.com.Bozzetti discussed both qualitative and quantitative differences between age- and cancer-related sarcopenia, even in terms of functional impairments [6]. In age-related sarcopenia, the most evident functional impairment is a loss of muscle strength, impacting daily activities. In contrast, patients with cancer-related sarcopenia often experience fatigue from minimal physical activity. New animal studies integrating genomic and proteomic analysis have compared the skeletal muscle response to cancer cachexia and aging in mice, suggesting that these two conditions have distinct protein signatures [16]. While these results require further validation in humans, they may imply the need for different treatments for age-related and cancer-related muscle loss. Importantly, muscle loss in cancer can occur independently of cancer cachexia, and these may also incur different conditions (low muscle mass alone versus low muscle mass in the context of cachexia). The latter manifests as a complex syndrome involving multiple body and system changes. Age-related sarcopenia responds well to increased physical activity, especially endurance exercises, and adequate nutrition, which can counteract the effects of aging on mitochondrial activity (content and function) and delay muscle wasting [10,13]. This better response to nutritional intervention and exercise can be attributed to the higher sensitivity of fast glycolytic muscle fibers to these stressors [13]. In turn, a multimodal approach, incorporating specialized/targeted nutrients/ingredients, anti-inflammatory or orexigenic drugs, and exercise, appears to confer the most benefits to patients with cancer-related sarcopenia. Ongoing research should further explore distinctions between age-related and disease-related sarcopenia, as well as cancer cachexia. This research should investigate the need for distinct definitions, assessments, and interventions tailored to the unique pathophysiological mechanisms and functional/clinical outcomes of each type. The discussion by Bozetti [6] and our team may underscore the importance of developing targeted strategies to address unique challenges posed by different forms of muscle mass loss. A one-size-fits-all approach is likely inadequate in this context. Acknowledgements S.M.P. and C.M.P. are partially funded through a Canada Research Chairs Program. Financial support and sponsorship None. Conflicts of interest M.C.G. has received honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, and Nestlé Health Science Brazil. A.J.C.J. has received honoraria and/or paid consultancy from Abbott Nutrition, Akros Pharma, Chugai Pharmaceutical, Fresenius Kabi, Nestlé Healthcare, Nutricia Danone, Rejuvenate Biomed, Reneo Pharmaceutical and Toray Industries. S.M.P. reports grants or research contracts from the US National Dairy Council, Canadian Institutes for Health Research, Dairy Farmers of Canada, Roquette Freres, Ontario Centre of Innovation, Nestle Health Sciences, Myos, National Science and Engineering Research Council, and the US NIH during the conduct of the study; personal fees from Nestle Health Sciences and nonfinancial support from Enhanced Recovery, outside the submitted work. C.M.P. has previously received honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Pfizer, AMRA Medical, and Novo Nordisk.

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