A counterintuitive perspective for the role of fat-free mass in metabolic health

This article stems from contradictory published results in the literature concerning the beneficial role of greater fat-free mass (FFM) on metabolic health.1-6 The widely accepted principle that greater FFM contributes to a better metabolic health overshadows available data supporting the opposite view. The objective of this article is thus to raise awareness and to urge the scientific community to take a fresh look at the association between FFM and cardiometabolic health.

The current state-of-the-art: where does it come from?

The role of FFM in metabolic health has been studied for decades. Work from Samuel Soskin dating as far back as the 1930's recognizes the role of muscle in the uptake and oxidation of glucose in diabetic individuals.7 Fast-forward to the 1980's, Miller et al. in 19848 and Szczypaczewska et al. in 19899 already reported a decreased insulin concentration following an oral glucose tolerance test in individuals who gained muscle mass following a strength training programme8 or those with greater muscle mass.9 Both groups had similar conclusions: ‘better glucose tolerance in body builders was associated with lower insulin concentrations supports the view that enlargement of muscle mass by training increases body insulin sensitivity’.9

Two main mechanisms are generally reported to explain observations like those of Miller et al.8 or Szczypaczewska et al..9 First, the relation between FFM and resting metabolic rate (RMR)10 has led to the logical assumption that a greater FFM, and therefore, a greater RMR, would protect against obesity and associated co-morbidities. Secondly, a classical study of DeFronzo et al.11 showed that muscle tissue contributes to the majority of glucose uptake in insulin-stimulated conditions. These results contributed to the notion that a greater FFM, possibly through increased energy expenditure and glucose uptake, will help maintain glucose homeostasis or insulin sensitivity. Accordingly, sarcopenia—the loss of muscle mass observed with aging—is thus deemed deleterious to metabolic health. In this context, interventions in favour of FFM gains are eagerly being studied and recommended, especially to older adults in whom sarcopenia is paralleled with an increase in cardiometabolic diseases prevalence. These recommendations are however provided broadly, irrespective of context and baseline FFM. A growing body of evidence suggests this could be suboptimal, if not harmful, in many instances.

‘Unexpected’ results

A recent publication by Hirasawa et al.1 showed that the way FFM is expressed leads to contrasting conclusions regarding the protective effect of FFM in individuals with type 2 diabetes (T2D). Park and Yoon2 and Scott et al.3 showed similar results for the metabolic syndrome (MetS).

There are three common ways to express FFM: in absolute terms (absolute FFM; kg), relative to body weight [FFM%; FFM (kg)/total body weight (kg) * 100], and relative to height (FFM index; kg/m²).

Considering the purported idea that low FFM is associated with deteriorated metabolic health, many interventional studies have focused on increasing FFM, notably through a resistance exercise programme. Results from these studies are however inconsistent. For instance, we observed that the loss of FFM was the only independent predictor of improvements in IS assessed with HOMA-IR after a 6 month intervention in a sample of 48 post-menopausal women.15 In contrast, Baldi et al. 16 found that improvements in HbA1c were inversely associated with changes in FFM in a sample of nine individuals with T2D who exercised for 10 weeks, which suggests a protective effect of FFM. Their results could have been confounded by medication, as Lee et al.17 have reported that insulin-sensitizing medication therapy could attenuate FFM loss observed in individuals with T2D. Last but not least, a recent meta-analysis of studies investigating the effect of resistance training in older individuals showed that, altogether, improvements in glycaemic control assessed with HbA1c were independent of variations in FFM,18 suggesting that the other mechanisms could be at play. In sum, it remains to be determined what the true role is of a large FFM in the development of cardiometabolic diseases, and, as such, if it is only an artefact or if this phenotype, and if its inherent characteristics are actually deleterious to metabolic health. Mechanistic studies are thus required to settle this ambiguity.

Potential mechanisms

Because type II fibres hold the greatest capacity for hypertrophy, a larger FFM is generally associated with greater percentage of type II and type IIx muscle fibres. It is interesting to note, however, that fibre typology has been associated with health status.19, 20 Fisher et al.19 have reported an inverse association between a high percentage of type II fibres, especially type IIx fibres, and IS measured with a clamp. This association extended to mean arterial blood pressure and low-density lipoprotein cholesterol concentrations.19 Furthermore, Gueugneau et al.20 reported larger type II muscle fibres in older individuals with MetS compared with healthy counterparts. These two studies suggest that having larger and a high relative quantity of type II fibres, particularly type IIx, may hold a role in cardiometabolic disease risk.

Aside from endurance athletes, in whom the athlete's paradox has been previously described, greater accumulations of intramuscular triglyceride has been associated with adverse metabolic outcomes such as IR, MetS, and T2D.20, 22 For instance, Gueugneau et al.20 showed that individuals with MetS had a larger proportion of muscle fibres area occupied by lipid droplets. Interestingly, while intramuscular triglycerides are generally stored in type I fibres to be used as an energy substrate, it was shown that older men with MetS had greater lipid accumulation in type IIx fibres than had healthy counterparts.20 This relation between fat infiltration and an altered metabolic health could be mediated by secreted factors, namely, ceramides, that are known to alter insulin signalling pathways.22

Muscle quality, typically evaluated with relative strength, is a major contributor to overall health.23-26 Indeed, results from a large cohort study in the US showed a significant association between higher relative strength and a more favourable cardiometabolic profile.25 It is interesting to note that while absolute strength increased significantly with weight status (from normal weight to obese) in all groups but women aged 40 to 59, relative strength significantly decreased with weight status.25 Similarly, Mesinovic et al.24 recently showed that individuals with MetS had lower muscle quality despite a larger FFM. They concluded that greater FFM does not grant a functional advantage, whereas muscle quality may be useful for identifying individuals with MetS who are at risk of functional declines.24 Supporting this notion are the results of Barbat-Artigas et al.26 who reported a negative association between muscle quality and FFM, and greater functional impairments with low relative strength.

To counter for a potential confounding effect of body composition on the relation between metabolic health and relative strength, Poggiogalle et al.23 studied metabolically healthy and unhealthy adult women matched for body composition. They reported greater relative strength in metabolically healthy women compared with unhealthy counterparts and a negative association between relative strength and HOMA-IR.23 Interestingly, the two major differences between groups were greater visceral adipose tissue and intramuscular fat accumulation in metabolically unhealthy women,22 supporting our previous assumption that a large FFM is not protective of the deleterious impact of intramuscular fat accumulation to muscle quality and health.

Taken as a whole, muscle quality, assessed as relative strength, seems to be a great predictor of metabolic health, while, in contrast, having a larger FFM does not seem to confer a protective effect.

Taking a step back

We first urge research groups to discuss their counterintuitive results in an effort to balance the current publication bias. Care must however be taken when reporting FFM, as different expressions may lead to contrasting conclusions. Studies using state-of-the-art methods for the quantification of body composition (e.g. dual-energy X-ray absorptiometry) should pay special attention not to use the percentage of FFM. Furthermore, sound results establishing the causal role of low FFM in metabolic diseases are insufficient, and several interventional studies show that improvements in metabolic health are independent of changes in FFM.18 Nevertheless, a great deal of research is still built on the premise that low FFM can lead to cardiometabolic diseases.

Considering the counterintuitive nature of the subject, studies investigating the mechanisms underlying the association between a large FFM index and deteriorated metabolic health would contribute to determine the exact role of FFM in metabolic health. Current data hint towards a potential role of microvasculature, muscle fibre-type distribution and size, fat infiltration, and FFM function, but elegantly designed studies are required to confirm our observations.

In conclusion, the wide recommendations to maintain or increase FFM in an effort to improve cardiometabolic health, regardless of baseline FFM, are based on unsubstantiated premises and could lead to suboptimal if not deleterious outcomes in some populations.