中国P站

The Hazard Ratio (HR) for the composite primary end point of death from cardiovascular cause, nonfatal Myocardial Infarction (MI) and nonfatal stroke was 0.80 (95% Confidence Interval (CI) 0.72-0.90; p<0.001) compared to placebo after weekly administration of subcutaneous semaglutide for nearly 3 and a half years in the semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) randomized controlled trial [1]. Hence, besides a 9.39% weight loss, semaglutide reduced Cardiovascular Disease (CVD) risk by 20% in subjects who, with a mean age of 61, Body Mass Index (BMI, kg/m2 ) of 33.5 and without Type 2 Diabetes (T2D), were receiving lipid-lowering medications, platelet aggregation inhibitors, beta-blocker, angiotensin-convertingenzyme or angiotensin-receptor blockers for a history of CVD 9 (MI 67.9%, stroke 17.9%, peripheral arterial disease 4.3% or 2 CVD). The striking findings of SELECT bolster the long-term administration of semaglutide for CVD risk reduction in late middle-aged or elderly subjects with overweight or obesity [2]. However, weight loss in any context decreases both fat free mass and skeletal muscle mass and strength with the later exposing patients with elevated BMI to sarcopenic obesity [3-5].

After a brief review of the prevalence and leading mechanisms of sarcopenic obesity, we examined the conflicting data regarding the effects of semaglutide on skeletal muscle mass and strength. Last, we underline the key role of skeletal muscle contraction in muscle protein synthesis and advocate for resistance exercise training for prevention of skeletal muscle weakness and atrophy during long-term use of semaglutide.

Sarcopenic obesity

The prevalence of skeletal muscle atrophy increases with age. Skeletal muscle mass declines by 4.7% per decade in men and by 3.7% per decade in women [4]. The prevalence of sarcopenia is ≥ 30% in subjects older than 60 years and reaches 66.6% in elderly Mexican American subjects which is not surprising given the rising rates of obesity and sedentary lifestyles in aging populations [6,7]. Of great importance for the detection of sarcopenia in obesity, skeletal muscle strength declines 2.5 times faster than skeletal muscle mass and handgrip testing lacks sensitivity for detection of sarcopenia as agerelated skeletal muscle mass decline in the lower limbs precedes agerelated skeletal muscle mass decline in the upper limbs.

The mechanisms of age-related loss of skeletal muscle mass include reduced daily activity with longer periods of inactivity, reduced levels of anabolic hormones, growth hormone, insulin growth factor 1, insulin and testosterone, increased glucocorticoid levels, accumulation of dysfunctional proteins and organelles and reduction in motor units and type II fibers with mitochondrial dysfunction and uncoupling to oxidative phosphorylation [5] (Figure 1). Increased baseline activity of mechanistic Target of Rapamycin Complex 1 (mTORC1) and the lack of mTORC1 fluctuation in elderly subjects decreases the sensitivity of the mTORC1 system to anabolic stimuli. Elderly subjects require twice the amount of high-quality protein for maximal stimulation of muscle protein synthesis than do young subjects.

 

Figure 1: Summary pathway of how mechanisms stemming from sedentary lifestyles in both obesity and aging lead to muscle atrophy and rising inflammation and oxidative stress. Increase in muscle atrophy causes increasing symptoms which further perpetuates muscle atrophy.

Obesity-related loss of skeletal muscle shares common mechanisms with age-related loss of skeletal muscle [7]. Omental and ectopic Adipose Tissue (AT) expansion heightens low grade systemic inflammation in elderly subjects. Enlarged white AT secretes proinflammatory cytokines that activate signaling pathways regulating skeletal muscle loss (nuclear factor ΚB, signal transducers and activators of transcription 3, Forkhead box transcription factors, Janus kinase). Skeletal muscle atrophy induces filament protein degradation with intra-muscular accumulation of lipids, triacylglycerol, and diacylglycerol resulting in myosteatosis and impairment of insulin signaling. Fatty oxidation in the mitochondria impairs oxidative phosphorylation and increases reactive oxygen species production. Oxidative stress leads to endoplasmic reticulum stress and unfolded protein response causing dysfunction of proteasomal degradation and autophagy. Insulin resistance promotes endothelial dysfunction, and hyperinsulinemia promotes fibrosis through mTORC1 and small mothers against decapentaplegic 2/3 activation of angiotensin converting enzyme. Briefly, the ongoing interplay between AT expansion/inflammation and myosteatosis fosters skeletal muscle anabolic resistance and loss of skeletal muscle mass.

Weight loss and skeletal muscle mass

A 12-week dietary restriction program led to a 10.5% weight loss, a 6.1% reduction in lower limb muscle mass, and a 10.0% reduction in lower limb muscle strength in 24 middle-aged Japanese subjects with mean BMI of 29.2 kg/m2 [3]. Although the muscle mass index increased after dietary restriction, any loss of skeletal mass is concerning as a low muscle mass is associated with mortality, morbidity and reduced quality of life. Generally, muscle mass loss accounts for 25% of total weight loss according to the quarter rule [8].

A recent roundtable meeting emphasized that the loss of skeletal muscle mass during administration of a Glucagon Like Peptide-1Receptor Agonist (GLP-1RA) for 1.5 years is equivalent to 20 years of age-related loss of skeletal muscle mass [9]. In addition, 40% of the reduction in body weight was due to loss of lean mass in the Semaglutide Treatment Effect of People with Obesity-1 (STEP-1) Randomized Controlled Trial (RCT). The decrease in skeletal mass index exceeded 40% of the total weight loss in 18% of 42 patients with T2D, Non-alcoholic Fatty Liver Disease (NAFLD), and a mean BMI of 38.8 kg/m2 after once-weekly subcutaneous semaglutide administration for 52-weeks. The weight loss was deemed to be healthy and favorable due to the progressive increase in the ratio of skeletal muscle mass over Visceral AT (VAT). A meta-analysis of 6 RCTs encompassing 1541 subjects with overweight, or obesity revealed that reduction in lean mass accounts for 0% to 40% of the total weight reduction. Of note, lean mass loss accounted for 40% of total weight reduction in the semaglutide unabated sustainability in treatment of type 2 diabetes (SUSTAIN 8) trial.

The semaglutide RCTs or retrospective studies that reported mild or no change in lean mass were of ≤ 6 months’ duration or did not report a loss of VAT. Subcutaneous or oral administration of semaglutide for 24-week resulted in fat mass reduction without lean mass compromise in 88 patients with T2D and BMI>30 kg/m². Oral administration of semaglutide for 6 months reduced body fat by 1.5 kg without significant changes in whole body lean mass and appendicular skeletal muscle mass in 25 Japanese patients with T2D and BMI of 29.3 kg/m2 . Similarly, oral administration of semaglutide for 3 months decreased fat mass without effect on the percentage of skeletal muscle mass in 48 patients with T2D and obesity. Last, weekly subcutaneous semaglutide for 6 months significantly reduced liver and skeletal muscle steatosis while maintaining skeletal muscle volume in 21 patients with NAFLD and T2D.

Experimentally, bimagrumab, a monoclonal antibody against activing A, the ligand of activin type II receptor preserved lean mass when administered in combination with semaglutide in diet-induced mice with obesity. Semaglutide may lessen obesity-related skeletal muscle atrophy by lowering the activity of the ubiquitin system with a reduction of atrogin-1 and muscle RING-finger protein 1 due to increased activity of sirtuin 1, an important regulator of skeletal muscle metabolism.

Prevention, recovery of skeletal muscle atrophy

Muscle contraction is a potent stimulus of muscle protein synthesis and organized bouts of repetitive skeletal muscle contractions are the logical approach to insufficient muscle protein synthesis. Unfortunately, resistance training is time consuming and requires discipline. A proposed approach that ties the price of GLP-1RAs for weight loss to proof of resistance exercise training may motivate subjects with elevated BMI to join and stick with the training. Such an approach combines the two most beneficial interventions for weight loss-preservation of functional autonomy and quality of life. Joint arthritis, a common hindrance to aerobic exercise in subjects with elevated BMI, may not prevent resistance exercise training to subjects with elevated BMI in a well-equipped facility. At variance with aerobic exercise, old age (>85 years) is not a limitation to resistance training with older participants deriving the same benefits that 65-75 years old participants experience. In brief 8-12 repetitions at 65% of one repetition maxima involving lower and upper limbs muscles at a minimum of two non-consecutive per week with the goal to reach 75% of maxima may prevent development and progression of sarcopenic obesity while long-term administration of GLP 1RA prevents weight regain.

GLP1-RA have demonstrated impressive outcomes in lowering body weight and cardiovascular disease risk. With loss of body weight also comes loss of skeletal muscle mass which may compromise the benefits of the therapy. The maintenance of skeletal muscle mass will strengthen the benefit of GLP1-RA therapy for weight loss. An approach that combines GLP1-RA treatment with repetitive exercise training across older adults may motivate individuals while stimulating development of muscle mass.

1. Lincoff A, Brown-Frandsen K, Colhoun H, Deanfield J, Emerson S, et al. (2023) . N Engl J Med 389: 24.

   [] [] []

2. Sattar N, Neeland I, McGuire D (2024) Circulation 149: 1621-1623.

   [] [] []

3. Kim B, Tsujimoto T, So R, Zhao X, Oh S, et al. (2017) Diabetes Metab Syndr Obes 10: 197-194.

   [] [] []

4. Mitchell WK, Williams J, Atherton P, Larvin M, Lund J, et al. (2012) Front Physiol 3: 260.

   [] [] []

5. Nunes EA, Stokes T, McKendry J, Currier B, Phillips S (2022) Am J Physiol Cell Physiol 322: 1068-1084.

   [] [] []

6. Prado CM, Batsis JA, Donini LM, Gonzalez MC, Siervo M (2024) Nat Rev Endocrinol 20: 261-277.

   [] [] []

7. Wei S, Nguyen TT, Zhang Y, Ryu D, Gariani K (2023) . Front Endocrinol (Lausanne) 14: 1185221.

   [] [] []

8. Henney AE, Wilding JPH, Alam U, Cuthbertson DJ (2024) Int J Obes 49: 369-380.

   [] [] []

9. Mechanick J, Butsch WS, Christensen S, Hamdy O, Zhaoping L, et al. (2024) . Obes Rev 26: e13841.

   [] [] []