Fibroblast growth factor 21, FGF21, is one of many proteins to emerge as a target for further research during the past few decades of investigation into the biochemistry of calorie restriction. The practice of calorie restriction, reducing calorie intake by up to 40% while maintaining optimal micronutrient levels in the diet, has been found to reliably slow aging and extend life span in most of the species and lineages tested to date. The effect size is much larger in short-lived species than in long-lived species such as our own, unfortunately, and this is generally true of all interventions that upregulate beneficial stress responses. Calorie restriction spurs greater activity in cellular housekeeping processes such as autophagy, and otherwise makes cells more efficient and resilient. The outcome is a slowing of near all measures of aging.
Because calorie restriction produces sweeping changes in the operation of metabolism, it has been a slow and expensive process to determine the important controlling mechanisms, genes, and proteins. That process still continues today, but more of a focus is placed on well-known areas of study, those discovered some years ago. FGF21 and surrounding biochemistry is one such area - and a complicated area it is too. FGF21 levels increase with age, but also with calorie restriction, which clearly slows aging. Effects and processes relating to FGF21 seem different in obese individuals versus those of normal weight, and different again in aging.
So far it seems a bit of a mess, which probably means that any sort of therapy resulting from this research will have to be narrowly targeted to specific situations and specific tissues. An example of work that might be heading in that direction, eventually, is the role of FGF21 in muscle, as outlined in the open access paper noted below. FGF21 appears to control the reduction in muscle mass following inactivity and starvation, but is also involved in the beneficial cellular housekeeping process of mitophagy, necessary for effective muscle maintenance and function. So even here there are multiple processes to consider, and which appear to stand somewhat in opposition to one another.
Exercise, nutritional changes, organelle dysfunction, and stress induce the systemic release of muscle-derived factors: cytokines (myokines) and metabolites (myometabolites) that exert autocrine, paracrine, or endocrine effects. Indeed, exercise preserves and ameliorates mitochondrial function and muscle metabolism, thereby affecting the release of myokines and metabolites, which might systemically counteract organ deterioration. In contrast, dysfunctional muscles can influence disease progression in other tissues.
The fibroblast growth factor 21 (FGF21) is a secreting myokine that can also be released in the bloodstream by other organs such as liver, heart, white adipose tissue (WAT), and brown adipose tissue (BAT). It is a starvation-like hormone with several metabolic functions aimed at overcoming nutrient deprivation by providing tissues with fuel. In skeletal muscle, FGF21 expression, in healthy conditions, is almost undetectable, and therefore, the circulating FGF21 is predominantly produced and released by the liver. In contrast, muscle-dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging. Moreover, FGF21 is a stress-induced myokine that has been proposed as a specific serum biomarker of muscle-specific mitochondrial disorders.
We and others recently demonstrated that in a muscle-specific OPA1 knockout animal model, characterized by mitochondrial dysfunction and by extensive muscle loss, the contribution of skeletal muscle to circulating FGF21 was predominant. In this model, FGF21 secreted from muscles mediates an integrated stress response that caused several systemic cell non-autonomous effects such as inflammation, metabolic alterations, and precocious senescence. Importantly, FGF21 deletion in OPA1 knockout muscles improved almost all systemic effects, while there was only a partial sparing of muscle mass. Injecting mice daily with exogenous FGF19, a closely related endocrine FGF member produced in the gut, increased skeletal muscle mass and strength. Remarkably, the skeletal muscle hypertrophy effects were not elicited by administrating FGF21. Thus, whether FGF21 is beneficial or detrimental for human health is still not clear, in part because the contribution of autocrine/paracrine-derived FGF21 signalling to muscle homeostasis has not been investigated yet.
In this study, muscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.
We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15-25% compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles, together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15%. Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals.
In summary, the current study elucidates by using gain and loss of function approaches, a novel role for FGF21 in the control of skeletal muscle mass through the regulation of the anabolic/catabolic balance. These findings are important for the understanding of the molecular pathways that control muscle mass. Moreover, this study also open several new avenues for future investigation to define the mechanisms mediated by FGF21 in the interplay between muscle and other tissues such as bones, heart, and WAT in whole body homeostasis.