Lean body mass loss – can we prevent it?

7th March 2024, A/Prof Chee L Khoo

Total body weight loss

There was some kerfuffle recently in the lay press about muscle loss with semaglutide. Great horror? Well, it doesn’t matter how you lose the weight. Any significant body weight loss will incur lean body mass loss (LBM). It’s not unique to GLP1-RA injections. Weight loss from bariatric surgery, dietary restrictions or just healthier eating will do the same. LBM declines. It all looks great on the scales but it is not without metabolic, physical or aesthetic downsides. Further, with subsequent weight regain (which most invariably do), only the fat is regained and there are further adaptive metabolic consequences. As LBM reduction is associated with reduced quality of life and increased mortality risk, clinician-supported weight loss plans should include a focus on minimising LBM loss in order to provide a comprehensive approach toward optimising overall health. What do we need to do?

The central role of muscle proteins

We usually think of muscles as the soft tissue lever that moves bones and joints. Perhaps less well recognised, muscle plays a central role in whole-body protein metabolism, which is particularly important in the response to stress. Maintenance of the protein content of certain tissues and organs, such as the skin, brain, heart, and liver, is essential for survival. In these vital organs, there is a constant breakdown of proteins which needs to be replaced. Muscles serve as the reservoir of amino acids to supply these organs via the blood. This is particularly the case in the fasting state. The muscle is also the source of amino acids for hepatic gluconeogenesis. Amino acids from food is incorporated into muscle protein to replace the reserves of amino acids lost in the fasting state. Under normal conditions, gains in muscle protein mass in the fed state balance the loss of muscle protein mass in the postabsorptive state.

The Muscle in disease states


We all know that obesity results from a positive energy imbalance over a prolonged time, which means that energy intake exceeds energy expenditure. Total energy expenditure is the sum of resting energy expenditure (REE), the thermic effect of food, and the energy expenditure related to activity. Under most circumstances, REE is the largest component of total energy expenditure. The resting metabolic requirements of splanchnic tissues, brain, and skin doesn’t vary much under normal conditions but the energy expenditure from muscle metabolism can vary considerably.

The average muscle mass of young, healthy males to range from 35 to 50 kg (1). In contrast, an elderly woman may have <13 kg muscle. Every 10-kg difference in lean mass translates to a difference in energy expenditure of ~100 kcal/d. A difference in energy expenditure of 100 kcal/d translates to ~4.7 kg fat mass/y. Thus, the maintenance of a large muscle mass and consequent muscle protein turnover can help to prevent obesity.

While excess energy intake is frowned upon, excess energy intake also leads to increase in muscle mass although the increase in muscle mass is not enough to offset the increase in fat mass leading to obesity. Increasing amino acid availability increases protein synthesis (muscle mass). Recent reports of improved body composition during weight loss with high-protein, hypocaloric diets support the notion of repartitioning of nutrient intake when protein turnover is stimulated (2). Of course, increase in muscle mass can lead to increase in REE.

Insulin resistance and T2D

Insulin is released to enable muscle to clear glucose from the plasma. Muscle insulin resistance

is a hallmark of the metabolic syndrome. When the increased insulin secretion is unable to keep up with the increased demands glucose intolerance ensues. Only in the later stage of diabetes does the pancreas lose the ability to secrete extra insulin in response to hyperglycaemia. Disruption of the normal rate of muscle glucose uptake by muscle is thus central to the onset and progression of diabetes (3).

Adipose tissue insulin resistance translates to increase free fatty acid in plasma. Elevated FFA reduces glucose uptake into muscles because of the inhibition of oxidation of glucose. Further, FFA (triacylglycerol) accumulation in muscles is associated with further muscle insulin resistance. Interestingly, obesity without IR is not associated with triacylglycerol deposition in muscles. It is thought that the accumulation of FFA in muscles is the result of a reduction in FFA oxidation from muscle mitochondrial oxidate function. One of the main causes of mitochondrial dysfunction is physical inactivity.                  


Whereas body weight and weight-bearing exercises provide a direct mechanical force on bones, the largest loads on bone actually come from muscle contractions (4). Correlations between grip strength and bone area, bone mineral content, and bone mineral density in both healthy athletes (5) and stroke patients (6) support the notion that muscle contractions play a significant role in bone strength and mass. Even the correlation between body weight and bone mass can be explained on the basis of the force exerted on bone by muscle contractions, in that it takes more force per unit area to move heavier bodies (4). Furthermore, changes in bone mass and muscle strength track together over the life span (4).

Maintenance of adequate bone strength and density with aging is highly dependent on the maintenance of adequate muscle mass and function. Skeletal muscle mass was correlated positively with bone mineral content and bone mineral density in MINOS Mediterranean Intensive Oxidant Study), a prospective study of osteoporosis and its determinants in men (7). Men with the least skeletal muscle mass also had increased risks of falls due to impaired static and dynamic balance, presumably at least in part because of a decrease in muscle strength (7).

The STEP 1 trial

1961 adults aged ≥18 years with body mass index (BMI) ≥27 kg/m2 with ≥1 weight-related comorbidity or BMI ≥30 kg/m2, without diabetes, were randomised to semaglutide 2.4 mg once-weekly or matched placebo (2:1) for 68 weeks, plus lifestyle intervention (8). Total fat mass, total lean body mass and regional visceral fat mass were measured using DEXA at screening and week 68.

The mean weight of the 140 participants were 98.4 kg. The semaglutide group lost an average of 15% body weight while the placebo group lost 3.6kg. This resulted in reductions from baseline with semaglutide in total fat mass (-19.3%) and regional visceral fat mass (-27.4%). Of note though, there was a 9.7% loss in total lean muscle mass from baseline. because of the greater fat loss than muscle loss, body composition (fat vs muscle mass) improved. Nonetheless, there was loss of muscles.

Preventing muscle loss

We can see from above the consequences of muscle mass. Exercise improves muscle function and, in some circumstances, increases muscle mass as well. exercise is more effective at preventing loss of muscle than of restoring lost muscle mass. Trying to restore muscle mass is much harder than preventing loss of muscle mass especially in older patients. Progressive loss of muscle mass and strength occurs throughout adult life, and in middle age the rate of loss is accelerated and maintained until old age. Intervention in middle age or younger ages is therefore necessary to offset the deleterious effects of sarcopenia in old age.


Dietary recommendations on adult protein intake doesn’t really take into account muscle mass or function as their endpoints. It was based on meta-analysis of nitrogen balance. In general, nitrogen is supposed to be a reflection of adequacy of protein intake to prevent muscle loss. However, the body does reduce nitrogen excretion under adverse metabolic conditions (e.g. starvation) making the assessment of adequate muscle mass or function inaccurate. There are direct measures of body composition, such as total body potassium or measurement of lean body mass by dual energy X-ray absorptiometry that are better reflections of muscle mass than are nitrogen balance studies.

There are ample relevant studies of the metabolism of muscle protein that support the concept that increasing protein intakes above current guidelines would benefit muscle. Muscle protein is directly affected by protein intake in the diet. High dietary protein intakes increase protein synthesis by increasing systemic amino acid availability (9). The amino acids absorbed as a result of the digestion of protein stimulate the synthesis of muscle protein and promote muscle protein synthesis in a dose-dependent way (10-12). Both muscle mass and strength are improved by increased availability of amino acids, even in the complete absence of activity in healthy young subjects confined to bed rest.

Recent studies in free-living elderly individuals indicate that an increased intake of amino acids improves the physical function and strength of muscle (13,14). The recent finding that daily supplementation of type 2 diabetic subjects with amino acids improves metabolic control and decreases HbA1c concentrations (15) is consistent with the expected benefits of stimulating muscle mitochondrial protein synthesis. Insulin sensitivity was also improved by amino acid supplementation above recommended protein intakes in healthy elderly subjects with varying degrees of insulin resistance (16).

The optimal intake of protein is still uncertain but based on acute metabolic studies of muscle metabolism, it could be as high as 1.8g protein/kg body weight/per day. Detrimental effects of protein intakes >2.0 g/kg/day has not been documented.

In summary, it is great to lose weight but losing muscle mass at the same can be detrimental to health and function. It is imperative that when we advocate weight loss in patients carrying extra weight, we try to minimise lean body mass by incorporating exercise (especially resistance exercises) and a higher protein intake.


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