Bariatric surgery has been a focus of intense research as an effective method to improve metabolic health, including skeletal muscle health. Four studies (21–24) investigated skeletal muscle transcriptome and/or proteome to provide a comprehensive and unbiased understanding of muscle adaptation following surgery. However, one study (24, 25) was excluded due to errors in transcriptomic analysis.

As shown in Table 2 , although the number of differentially expressed genes varied considerably between obese and healthy lean groups, as well as between pre- and post-surgery conditions, all studies consistently reported the enrichment of mitochondria-related processes or functions. Furthermore, these studies investigated the transcriptomic and/or proteomic responses at 3 months (23), 6 months (22), and 1 year (21) after bariatric surgery, respectively. The variation in results across studies may indicate a gradual restoration of mitochondrial function over time. Campbell (23) found that oxidative phosphorylation and the citrate cycle were downregulated in obese patients prior to surgery, with these processes remaining unchanged 3 months post-surgery. However, improved mitochondrial function was observed at 6 months in Barres’ study (22) and at 1 year in Barberio’s study (21) following RYGB. Nonetheless, it is important to note that the small sample sizes and diverse approaches employed in transcriptomic/proteomic analysis may have contributed to the observed differences in results. Therefore, further investigation is warranted to reanalyze and synthesize the omics data from these studies using standardized bioinformatic methods before drawing definitive conclusions.

Mitochondrial content typically serves as an indicator of mitochondrial oxidative capacity. While transmission electron microscopy (TEM) is considered the gold standard for assessing mitochondrial content, alternative methods utilizing mitochondrial biomarkers are often employed for convenience. Larsen et al. (26) demonstrated that cardiolipin and citrate synthase activity (CSA) ranked as the top two strongest markers associated with mitochondrial content. The activity or content of several respiratory chain components, which are also closely linked to mitochondrial content (26), will be discussed in other sections of this article. In this section, we reviewed studies employing TEM, cardiolipin, or CSA to elucidate the trends in mitochondrial content adaptation.

In Table 3 , four studies (14, 24, 27, 28) were included, with two of them (14, 24) incorporating a healthy control group. Mitochondrial content (CSA) in the obese group did not significantly differ from that of the healthy control group. Although many studies have illustrated an association between lower muscle mitochondrial content and obesity (29–32), it is noteworthy that not all obese individuals exhibited reduced mitochondrial content (33–36). In addition to obesity, other factors such as age, physical activity and genetics may also influence mitochondrial content (17).

Regarding the effects of bariatric surgery on mitochondrial content, studies employing different methods have yielded varied results. Gancheva (24), using TEM, reported a decrease in mitochondrial content two weeks post-surgery, followed by a partial recovery that did not return to presurgical levels 52 weeks after surgery (RYGB or SG). This study also found an initial decrease in CSA at week 2, which then stabilized close to baseline levels from week 12 onward. Lund (28) and Kristensen (14), who did not assess CSA in the immediate post-surgery period as Gancheva, reported stable CSA levels after RYGB over time. In contrast, Mehnert’s study (27) indicated an increase in cardiolipin, reflecting mitochondrial content, one year after BPD procedure. These discrepancies across studies are likely due to differences in sample size and surgical procedures. Although Gancheva (24) used TEM, the gold standard measurement, the interpretation should be approached with caution given the small sample size of only two subjects. On the other hand, the CSA studies included larger cohorts and consistently showed stable trends across different investigations, making the results more compelling. For the cardiolipidin study, in addition to the relatively small sample size, other researchers suggested that BPD may exert greater metabolic improvements than RYGB (8), which may explain the more pronounced improvements of mitochondrial content following the surgery.

Mitochondria exist as interconnected and mobile networks, responding to cellular demands and environmental factors through ongoing fusion-fission dynamics (37). The fusion process is regulated by Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), and Optic Atrophy 1 (OPA1) (38), while the fission process is mediated by dynamin-related protein 1 (Drp1) and Fission 1 (Fis1) (39). In addition to these biomarkers, mitochondrial dynamics can be directly assessed through morphological image processing. Abnormal mitochondrial dynamics are strongly associated with various diseases and pathologies (40). In the context of obesity, emerging evidence from animal studies indicates that obesity adversely affects muscle mitochondrial dynamics, characterized by increased expression of fission processes (41) and decreased expression of fusion processes (42), resulting in fragmented mitochondrial networks. In this section, we first reevaluated the differences in mitochondrial fission-fusion dynamics between obese and lean subjects in studies that included a healthy control group. Subsequently, we reviewed the effects of bariatric surgery on mitochondrial dynamics.

Seven studies (14, 24, 43–47) were included ( Table 4 ), three of which incorporated a healthy control group (14, 24, 46). The majority of these studies corroborated the detrimental impact of obesity on muscle mitochondrial dynamics. Morphological assessments revealed more isolated mitochondria and fragmented mitochondrial networks in obese individuals (14, 46). Among the studies using biomarkers, Gancheva (24) and Kristensen (14) both demonstrated impaired mitochondrial dynamics in obese participants; however, their findings differed: Gancheva (24) reported reduced mitochondrial fusion (decreased Mfn2 and Opa1) with unchanged fission activity (unchanged pDrp1 and Fis1), while Kristensen (14) obeserved increased fission (elevated Drp1) alongside unchanged (unchanged Mfns and Opa1) or elevated fusion (elevated Mfns) in obese patients. Conversely, Kugler (46) found no difference in mitochondrial dynamics at the protein and mRNA levels of markers between obese and lean groups, despite the impairments in mitochondrial networks through imaging. Noably, Kugler’s study cultured myotubes derived from human skeletal muscle for 7 days before testing; however, the culture medium lacked appropriate components to simulate the extramyocellular lipid environment typical of in vivo skeletal muscle cells. Other in vitro studies have shown that excess palmitate was a primary factor inducing mitochondrial fragmentation in differentiated C2C12 muscle cells (41). Therefore, the absence of the extramyocellular lipid environment in Kugler’s medium may account for the discrepancies at the biomarker level.

As presented in Table 4 , most studies suggested that bariatric surgery improved mitochondrial dynamics in human skeletal muscle. Mitochondrial morphology in myotubes from obese individuals showed improvement in “individual non-networked mitochondria” and “branch length per network” 7 months post-RYGB (46). Concurrently, a reduction in Drp1 phosphorylation and Drp1 gene (DNM1L) expression, indicative of decreased mitochondrial fission processes, was observed at the same time point (46). Kristensen (14) observed a diminished expression of the mitochondrial fission marker Fis1 at 1.5 years post-surgery, while other research (24, 44, 45, 47) reported a significant upregulation of mitochondrial fusion markers, particularly Mfn2 at protein or mRNA levels, from three months to two years after surgery. While the evidence above consistently confirmed the beneficial effects of bariatric surgery on mitochondrial dynamics, certain details should not be overlooked. In contrast to Kristensen’s (14) observation regarding Fis1, Gancheva (24) found an increase in Fis1 levels two years post-surgery. This discrepancy may arise from the different units of measurement used: Gancheva (24) reported the raw test results, while Kristensen (14) normalized results to CSA relative to the first time point (PRE(A)). Additionally, Hernández-Alvarez (45) investigated the effects of bariatric surgery on Mfn2 specifically in T2D obese patients, while other studies either included only Non-T2D obese patients or analyzed T2D and Non-T2D obese patients together. Interestingly, Hernández-Alvarez’s study (45) found that, unlike the increase in Mfn2 observed in Non-T2D obese patients postoperatively (43–45, 47), Mfn2 decreased in T2D obese patients after surgery. This suggests that the diabetic state may independently affect the outcomes of bariatric surgery, highlighting the need for further research to elucidate the underlying mechanisms.

Mitochondrial respiration is the final stage of cellular respiration, during which substrates are oxidized to produce ATP in the coupled state or dissipated as heat in the uncoupled state. These processes are closed linked to the oxidative phosphorylation system (OXPHOS), the tricarboxylic acid (TCA) cycle, and uncoupling activities within the mitochondria. While the expression levels of specific proteins and genes may indicate mitochondrial respiratory function, direct assessment of oxygen consumption rates through respirometry provides a more comprehensive evaluation of mitochondrial respiration capacity (48). This section provided an overview of research on mitochondrial respiration remodeling following bariatric surgery with two parts: (i) the main components of mitochondrial respiration, and (ii) mitochondrial respiration capacity.

Following bariatric surgery, glucose and lipid metabolism in skeletal muscle improve significantly, as evidenced by a marked reduction in intramuscular triglycerides (27, 56, 67) and a substantial increase in skeletal muscle insulin sensitivity (43, 47, 56, 67, 68). As the primary site for the oxidation of carbohydrates and lipids in skeletal muscle, mitochondrial glucolipid markers may elucidate the mechanisms by which bariatric surgery enhances skeletal muscle metabolic health. This section reviewed the changes in mitochondrial markers associated with glucolipid metabolism following bariatric surgery.

In Table 9 , eight studies (22, 28, 47, 67–71) reported six key glucolipid metabolism markers within skeletal muscle mitochondria following bariatric surgery. Overall, although bariatric surgery has a well-established positive effect on skeletal muscle health, the trends observed in mitochondrial biomarkers across current studies are inconsistent. Acetyl-CoA carboxylase 2 (ACC2) is the most frequently reported marker. This mitochondrial enzyme is crucial for regulating fatty acid oxidation capacity (72) and is modulated by phosphorylation (73). In its non-phosphorylated form, ACC2 catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, which can inhibit the activity of carnitine palmitoyltransferase 1 (CPT1) through allosteric inhibition. This inhibition prevents the transport of long-chain fatty acyl-CoAs into the mitochondria, thereby reducing fatty acid oxidation (74). Three studies (67, 68, 71) found a significant decrease in ACC2 mRNA expression following bariatric surgery, with one study also reporting a marked reduction in its product, malonyl-CoA (67). This suggests that the transport of long-chain fatty acyl-CoAs into skeletal muscle mitochondria is enhanced post-surgery, leading to an increased capacity for lipid oxidation. Hinkley et al. (69) observed a similar trend regarding ACC2 phosphorylation. Their study found that the ratio of phosphorylated ACC2 increased one month post-surgery and returned to pre-surgery levels by seven months post-surgery, indicating that skeletal muscle mitochondria maintain or enhance their ability to oxidize fat following bariatric surgery. However, studies investigating CPT1B, the target of malonyl-CoA allosteric inhibition, did not indicate enhanced lipid oxidation capacity of skeletal muscle mitochondria after surgery. Three studies (47, 68, 70) demonstrated that, within 3-18 months post-bariatric surgery, CPT1B expression either decreased or remain unchanged. Additional findings include the unchanged activity of hydroxylacyl-CoA dehydrogenase, a key enzyme involved in fatty acid β-oxidation (75), following bariatric surgery (28). Similarly, the mRNA levels of pyruvate dehydrogenase kinase 4 (PDK4), an indicator of enhanced fat utilization (76), either deecreased or remained stable post-surgery (22, 70). Besides its role in lipid metabolism, PDK4 also inhibits glucose utilization (76). The unchanged or down-regulated mRNA levels of PDK4 following bariatric surgery suggest glucose metabolism was not further suppressed and may have been improved. Furthermore, hexokinase 2 (HK2), a mitochondrial enzyme that catalyzes the phosphorylation of D-glucose to D-glucose 6-phosphate (77), has also been shown to remain unchanged after bariatric surgery (70). These findings highlight the complexity of mitochondrial glucolipid adaptations following bariatric surgery and underscore the need for further research to clarify the relationships between these metabolic markers.

By reviewing of the included studies, we have clarified the impact of bariatric surgery on mitochondrial remodeling in skeletal muscle. Some discussion on the potential mechanisms of mitochondrial remodeling has already been provided in the mitochondrial dynamics section, specifically regarding changes in Mfn2, Drp1, and Fis1 that affect mitochondrial fusion and fission. From a broader perspective, we will discuss other possible mechanisms influencing skeletal muscle mitochondrial remodeling following bariatric surgery.

Weight loss is the most significant outcome of bariatric surgery; however, improved skeletal muscle mitochondrial function is not necessarily associated with weight loss. Mitochondrial respiratory capacity in skeletal muscle may remain unchanged or improve post-surgery, whereas caloric restriction-induced weight loss can lead to a decline in mitochondrial respiratory capacity (78, 79). One possible explanation for this discrepancy lies in their differing impacts on the gut microbiome, which has been shown to closely correlate with mitochondrial content and function in skeletal muscle (80). Research by Lahiri et al. (81) indicated that, despite similar weight loss, there were significant differences in gut microbiome composition between caloric restriction and surgical treatment. Bariatric surgery improved the obesity-associated gut microbiota composition, shifting it toward a lean microbiome phenotype. This finding also highlights the unique advantages of bariatric surgery in metabolic disease management.

Epigenetic modifications may also play a role in how bariatric surgery influences mitochondrial remodeling in skeletal muscle. Barres et al. (22) found that bariatric surgery reduced promoter methylation of proliferator-activated receptor γ coactivator-1α (PGC1α) in skeletal muscle, resulting in an increase in PGC1α mRNA expression. PGC1α is primarily associated with mitochondrial biogenesis and oxidative capacity, and enhanced expression of PGC1α has been shown to improve mitochondrial oxidative capacity (82). Other studies (45, 47, 69) have similarly confirmed the elevated expression of PGC1α post-surgery. Therefore, the downregulation of methylation in the PGC1α promoter, leading to increased PGC1α expression in skeletal muscle, may represent one of the mechanisms through which bariatric surgery enhances mitochondrial function.

In general, bariatric surgery can improve mitochondrial function in skeletal muscle among obese patients; however, the impact of bariatric surgery on mitochondrial content and respiratory capacity remains controversial. Exercise has been recognized as the most effective behavioral intervention for enhancing mitochondrial health (83). To optimize the improvement of skeletal muscle mitochondrial function and metabolic health, a regular exercise program should be integrated into post-surgical care as a complementary therapy.

We have noted a close relationship between certain mitochondrial biomarkers affected by bariatric surgery and health indicators. These molecules may serve as potential therapeutic targets for further research. Kugler et al. (46) found that the level of phosphorylated Drp1 was significantly negatively correlated with glucose oxidation in response to insulin stimulation. Subsequent animal studies (84) demonstrated that skeletal muscle-specific Drp1 gene partial knockout significantly improved insulin sensitivity in obese mice. Another biomarker related to mitochondrial dynamics, Mfn2, exhibited a significant positive correlation with glucose utilization across several studies (43–45). Correspondingly, animal models with partial gene knockout of Mfn2 in skeletal muscle showed impaired glucose tolerance and insulin resistance (85), while overexpression models displayed moderate muscle hypertrophy without pathological changes (86). These two molecules have been preliminarily validated as potential therapeutic targets. In contrast, while ACC2 gene expression also changes significantly after surgery, its impact on metabolic health is limited. Rosa et al. (67) found that the post-surgical changes in ACC2 gene expression were positively correlated with variations in fasting insulin levels and intramuscular triglycerides. However, skeletal muscle-specific ACC2 knockout animal models did not exhibit metabolic abnormalities, indicating that the absence of ACC2 in skeletal muscle has a limited impact on metabolism (87). Given the broad and profound effects of bariatric surgery, many mitochondrial biomarkers related to the surgery could be carefully explored as potential therapeutic targets for obesity and related metabolic disorders.

As discussed above, there are certain limitations within current research. First, methodological inconsistencies in measuring mitochondrial respiratory capacity are prevalent, specifically in the following areas (63) (i) inconsistent terminology for mitochondrial respiratory states and rates across studies; (ii) substantial differences in experimental conditions (e.g., temperature, pH, substrate concentration) and methods (e.g., sample preparation, measurement instruments); and (iii) challenges in data normalization and standardization. These methodological discrepancies can significantly obscure the findings. Future researchers could refer to the standardized protocols proposed by MitoEAGLE (63), a global network project in mitochondrial physiology research, to address these methodological issues. Second, physical activity, a crucial factor influencing mitochondrial function, is often overlooked. Without clear data on patients’ physical activity levels before and after bariatric surgery, assessing the surgery’s impact on skeletal muscle mitochondrial remodeling becomes challenging. Future studies should adhere to standardized reporting of physical activity data. Physical activity levels can be measured using questionnaires such as the International Physical Activity Questionnaire (IPAQ) or, more simply, with smartphone step-tracking functions.

In addition to these primary issues, the influence of different surgical procedures and gender difference on skeletal muscle remodeling post-bariatric surgery warrants further investigation. Our review indicates that various surgical techniques may differentially impact mitochondrial content in skeletal muscle post-surgery. Although different metrics were used, BPD appears to promote a greater increase in mitochondrial content post-surgery compared with RYGB and SG. However, as the two most widely used bariatric procedures, the effects of SG and RYGB on skeletal muscle mitochondria post-surgery are unknown and require further investigation. Additionally, gender influences skeletal muscular mitochondrial function, with females typically exhibiting higher intramuscular lipid exposure yet stronger antioxidant capacities (88). Existing studies are either entirely female-focused or combine both genders, making it difficult to evaluate gender-specific effects on skeletal muscle remodeling post-surgery. Investigating these issues will not only provide a basis for optimizing surgical approaches but also support personalized postoperative management strategies, helping patients achieve more sustained improvements in metabolic health.