The scale of the clinical associations is striking. Excessive intramuscular fat has been linked not only to sarcopenia in older adults but also to coronary microvascular dysfunction, where it independently predicts adverse cardiovascular outcomes. It is tightly connected to insulin resistance and type 2 diabetes, with intermuscular adipose tissue shown to directly impair the insulin sensitivity of muscle tissue. In metabolic dysfunction-associated steatotic liver disease, greater intramuscular fat correlates with disease severity, visceral adiposity and even gut dysbiosis. Worsening muscle quality is associated with increased mortality in chronic kidney disease, poorer outcomes in cirrhosis, and complications after transplantation. In oncology, myosteatosis has emerged as an independent prognostic marker across multiple malignancies, predicting survival in ways that simple muscle volume measurements cannot capture.

Part of the appeal of intramuscular fat as a biomarker lies in its sensitivity to change. While ageing may cause roughly five to ten per cent muscle loss over a decade, the fat fraction within muscle can double over the same period, explaining functional decline far better than muscle mass alone. Sedentary behaviour or immobilisation quickly increases intramuscular fat content, whereas regular physical activity helps maintain lean muscle quality. Fatty infiltration in the thigh and calf muscles of older people correlates with poorer balance and increased falls risk, and in neuromuscular disorders such as muscular dystrophies, MRI fat fraction mapping has already become an invaluable outcome measure for tracking disease progression.

Yet the term myosteatosis conceals a biological complexity that the review works hard to untangle. At the microscopic level, intramyocellular lipids are stored as droplets within muscle fibres, serving as a readily mobilised energy reserve. When accumulation exceeds the storage capacity of fibres — a state known as lipotoxicity — insulin signalling is impaired and inflammatory pathways are activated. Crucially, other lipid species such as diacylglycerols and ceramides are metabolically bioactive, suggesting that lipid composition, not merely quantity, matters when interpreting the biomarker. Extramyocellular lipids occupy the space between fibres and fascicles, while intermuscular adipose tissue lies between muscle groups beneath the deep fascia. Each compartment carries different biological meaning, and the relative contribution of each to a measured fat signal depends on the imaging modality and its resolution.

That measurement challenge sits at the heart of the field. Magnetic resonance imaging offers a spectrum of approaches, from subjective visual grading systems such as the Goutallier scale, still widely used in orthopaedic surgical planning, to quantitative Dixon-based techniques that exploit the chemical shift between water and fat protons. Multi-echo Dixon sequences correct for field inhomogeneities, relaxation effects and spectral complexity, yielding the proton density fat fraction — a standardised measure validated against spectroscopy and increasingly applied in clinical trials. Magnetic resonance spectroscopy remains the gold standard for biochemical specificity, uniquely distinguishing intramyocellular from extramyocellular lipids, and phosphorus spectroscopy can probe mitochondrial energetics through high-energy phosphate metabolism. However, spectroscopy suffers from low spatial resolution, voxel placement variability and labour-intensive acquisition, confining it largely to mechanistic research.

Computed tomography offers a pragmatic alternative. It infers fat content from tissue radiographic density expressed in Hounsfield units, with lean muscle typically measuring around 50 to 60 HU and fat-infiltrated muscle appearing progressively less dense. Standardised assessment at the third lumbar vertebral level, using thresholds such as mean density below 41 HU for individuals with a body mass index under 25, has proven effective in predicting cancer survival and mortality in kidney and liver disease. Artificial intelligence, particularly convolutional neural networks, now enables fully automated segmentation of muscle and adipose tissue from routine clinical scans, reducing observer variability and opening the door to large-scale population studies. But CT carries ionising radiation, cannot separate lipid compartments, and is confounded by fluid retention and glycogen variation, which can lower muscle density independently of fat.

Ultrasound rounds out the toolkit as a portable, inexpensive, radiation-free option. Increased echogenicity indicates higher fat or fibrous tissue content, and quantitative echo intensity correlates with MRI-estimated intramuscular fat and with muscle performance. Ultrasound also captures muscle architecture — fascicle length and pennation angle — in a single bedside examination. Its weaknesses are reproducibility and specificity: measurements are sensitive to operator technique, probe pressure, transducer frequency and machine settings, and ultrasound cannot distinguish fat from fibrosis or resolve individual lipid compartments. The SARCUS consensus has defined anatomical landmarks for 39 muscles to improve acquisition consistency, and a cadaver-validated three-point grading system for sarcopenia has shown excellent reliability, but inter-device variability remains a barrier to multicentre trials.

Perhaps the most provocative finding in the review is that ‘normal’ intramuscular fat is anything but uniform. Even in healthy individuals, different muscles harbour inherently different fat content: the gluteus maximus typically contains around fifteen per cent fat in young men and twenty per cent in young women, while neighbouring hip abductor muscles hold only eight to ten per cent. Ageing amplifies these differences dramatically — quadriceps muscles in older men contain four to five times more fat than those of young men, despite only modest differences in muscle cross-sectional area. Sex differences appear partly mediated by conditioning: recreational cyclists of both sexes showed equivalent gluteal fat of roughly twelve per cent once body size and activity were accounted for. Ethnicity adds further complexity, with South Asian children carrying higher intramyocellular lipid than their peers, and African American and Hispanic adults accumulating more intramuscular fat for a given body size — patterns that may partly explain population differences in insulin resistance and that render European-derived reference values non-universal.

The athlete’s paradox crystallises why context is everything. Endurance athletes can carry high intramyocellular lipid yet remain exquisitely insulin sensitive, because their lipid droplets sit within oxidative fibres, are smaller, and are closely apposed to mitochondria, supporting rapid turnover. The same lipid levels in sedentary individuals signal insulin resistance and frailty. This U-shaped relationship — high fat in insulin-sensitive athletes, low fat in insulin-sensitive non-athletes, high fat again in insulin-resistant states — means intramuscular fat cannot be treated as a uniform risk factor. The review suggests composite indices, such as a muscle quality index integrating fat with strength or power measures, and points to emerging mass spectrometry imaging studies that map lipid species and their microregional organisation within muscle histology.

Encouragingly, intramuscular fat is modifiable. A single bout of cycling depletes intramyocellular lipid by roughly twenty-four per cent in exercised muscles. Twelve months of moderate physical activity in older adults prevented the thigh muscle fat gain seen in sedentary controls, who accumulated around eighteen per cent more fat while the active group gained only two per cent — and the exercisers avoided the strength loss their sedentary peers suffered. Meta-analyses of randomised trials show combined aerobic and resistance training reduces fat infiltration most robustly when paired with weight loss. Caloric restriction and bariatric surgery consistently reduce ectopic fat depots, though rapid weight loss risks lean mass loss unless protected by resistance training and adequate protein. Most recently, glucagon-like peptide-1 receptor agonists such as liraglutide and semaglutide have shown modest but significant reductions in intramuscular fat, though concerns persist because these drugs also reduce absolute muscle mass, raising sarcopenic obesity risks in older or frail patients. Before intramuscular fat can join bone density and liver fat as a routine clinical measure, the field needs standardised protocols, multi-ethnic longitudinal cohorts to define age-, sex- and ethnicity-specific reference ranges, and consensus on what constitutes a clinically meaningful change. If those hurdles fall, clinicians may one day stratify risk across sarcopenia, cirrhosis and cancer cachexia — and track whether an intervention genuinely improves muscle quality rather than merely mass.

Subject of Research: Intramuscular fat accumulation (myosteatosis) as a biomarker of skeletal muscle health and chronic disease

Article Title: Intramuscular Fat as a Biomarker of Muscle Health: Strengths, Limitations and Open Challenges

Article References: Spence, C., Belzunce, M. A., Di Laura, A., Henckel, J., & Hart, A. J. (2026). Intramuscular Fat as a Biomarker of Muscle Health: Strengths, Limitations and Open Challenges. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70389. https://doi.org/10.1002/jcsm.70389

Image Credits: AI Generated

DOI: 10.1002/jcsm.70389

Keywords: intramuscular fat, myosteatosis, sarcopenia, muscle quality, Dixon MRI, magnetic resonance spectroscopy, computed tomography, ultrasound, insulin resistance, athlete's paradox, GLP-1 receptor agonists, biomarker standardisation

The core of the authors’ argument is that losing lean mass is not the same thing as losing functional muscle. When any person loses weight, whether through diet, surgery, or medication, the body sheds both fat and lean tissue because a lighter body simply demands less structural and metabolic support. A recent meta-analysis cited in the perspective found that lean mass accounted for roughly 25 to 39 percent of the total weight lost with incretin-based therapies, a proportion broadly comparable to the 26.2 percent observed with conventional lifestyle interventions. In other words, the fraction of weight loss coming from lean tissue during pharmacotherapy looks remarkably similar to what happens when patients lose weight the old-fashioned way, suggesting that the phenomenon reflects physiological body composition remodeling rather than a drug-specific pathology.

Real-world comparative data strengthen this interpretation considerably. In a cohort of 3,066 individuals, fat-free mass decreased by 11.7 percent after bariatric surgery but by only 3.3 percent during treatment with semaglutide or tirzepatide over 24 months. Meanwhile, fat mass fell far more dramatically, by 49.7 percent in the surgical group and 18.0 percent in the medication group. Crucially, in both groups the ratio of fat-free mass to fat mass improved, meaning patients ended up with a more favorable body composition than they started with. The authors contend that this pattern, in which adipose tissue declines disproportionately while most lean tissue is preserved, is difficult to reconcile with the notion of treatment-induced muscle wasting, although they acknowledge that a treatment-specific contribution cannot be entirely excluded.

Body composition sub-studies from the major clinical trial programs reinforce the point. In the STEP trials of semaglutide and the SURMOUNT program of tirzepatide, investigators documented marked reductions in total fat mass alongside preservation of most lean mass, yielding a net improvement in the lean-to-fat mass ratio despite modest absolute declines in lean tissue. Similar findings have emerged with oral semaglutide in people with type 2 diabetes, where fat mass declined significantly while skeletal muscle index and lean body mass remained largely unchanged. Taken together, these data suggest that incretin therapies preferentially strip away the tissue that is causing harm while leaving the metabolically active machinery of muscle largely intact.

Perhaps the most provocative element of the perspective is its argument that obesity itself damages muscle quality, so that weight loss may actually improve the muscle that remains. Excess adiposity promotes the accumulation of fat within muscle fibers, chronic low-grade systemic inflammation, mitochondrial dysfunction, and reduced contractile efficiency, producing muscle that is quantitatively larger but functionally inferior. Intentional weight loss appears to reverse several of these abnormalities: even as lean mass declines modestly, reductions in intramuscular lipid infiltration and inflammation, together with improvements in oxidative capacity, may enhance the functional quality of skeletal muscle. The authors invoke a memorable formulation to capture this idea: a smaller muscle is not necessarily a weaker muscle, and may in fact be metabolically healthier and more efficient than the enlarged, fat-infiltrated muscle it replaces.

The strongest evidence against the sarcopenia hypothesis comes from measurements of what muscles actually do. Across obesity trials, incretin therapy has consistently improved exercise capacity, physical performance, and mobility rather than degrading them. Multiple STEP studies demonstrated meaningful improvements in physical functioning and obesity-specific quality of life following semaglutide treatment, outcomes that are difficult to square with clinically relevant muscle loss, which would be expected to impair rather than enhance function. Evidence from bariatric surgery points in the same direction: despite substantial reductions in lean body mass during the first postoperative year, relative muscle strength, gait speed, chair-stand performance, and overall physical function consistently improve, changes long recognized as reflecting favorable physiological remodeling. Subgroup analyses of the major obesity trials have also shown comparable efficacy and safety of incretin therapies in participants aged 65 and older compared with younger adults, supporting their use in appropriately selected older patients.

None of this means the field can afford complacency, and the authors are careful to delineate who remains genuinely at risk. Sarcopenic obesity, the coexistence of excess adiposity with impaired muscle quantity, quality, and function, is a well-recognized clinical entity associated with frailty, disability, hospitalization, cardiometabolic complications, and increased mortality, and current consensus definitions emphasize function rather than mass alone. Older adults and individuals with pre-existing sarcopenia or frailty, low muscle strength, chronic inflammatory, kidney, or cardiovascular disease, prolonged physical inactivity, or inadequate nutritional intake are inherently more vulnerable to declines in muscle health regardless of which weight-loss strategy is employed. For these populations, the authors advocate a risk-stratified approach: baseline assessment and longitudinal monitoring of muscle strength and physical performance, attention to the rate of weight loss, and individualized nutritional support, whereas patients with preserved muscle reserve can generally be followed with routine clinical care.

The practical prescriptions that follow are grounded in established evidence rather than speculation. Adequate dietary protein intake, tailored to age, renal function, and nutritional status, should accompany pharmacological weight loss, and progressive resistance exercise should be regarded as an essential component of obesity treatment rather than an optional adjunct, complemented by aerobic activity to optimize cardiometabolic health. These recommendations align with current obesity guidelines and with studies showing that resistance training attenuates lean mass loss while improving muscle strength and physical performance during intentional weight loss. The authors also situate the muscle debate within the broader risk-benefit calculus of incretin therapy, noting that semaglutide has been shown to reduce major cardiovascular events in people with overweight or obesity and established cardiovascular disease, and that recent phase 3 data demonstrate benefits in metabolic dysfunction-associated steatohepatitis. Emerging analyses suggest these cardiovascular gains may not be fully explained by the magnitude of weight loss, pointing to anti-inflammatory and direct receptor-mediated effects that extend beyond adiposity reduction.

Significant knowledge gaps remain, and the perspective is candid about them. Long-term data extending beyond the duration of current clinical trials are limited, and the effects of incretin therapies in people with established sarcopenic obesity have barely been studied. The authors call for future research to prioritize muscle quality and function over lean mass alone, to establish standardized definitions of clinically meaningful muscle loss, and to test whether combining incretin drugs with resistance exercise, nutritional optimization, and emerging anabolic agents targeting the myostatin-activin signaling pathway can further optimize body composition and functional outcomes in high-risk groups. Skeletal muscle is also an endocrine organ, releasing myokines that regulate glucose and energy metabolism across organs, so substantial loss of functional muscle tissue could carry metabolic consequences beyond strength and mobility, a consideration that keeps the question scientifically live even as the clinical picture looks reassuring.

The conceptual shift the authors propose is ultimately about how medicine should judge success in obesity treatment. The field has already moved from counting kilograms to analyzing body composition, and the next step, they argue, is to focus on patient-centered outcomes: whether treatment leaves people healthier, stronger, and more functional. By that standard, the available evidence suggests that incretin therapies are restoring physiology rather than eroding it, preferentially removing the fat that drives disease while preserving, and possibly improving, the quality of the muscle that remains. Rather than viewing every kilogram of lean tissue lost as evidence of harm, clinicians should ask the harder and more meaningful question of whether patients can move better, live longer, and feel healthier, and on current evidence, the answer for most appears to be yes, provided that protein intake, resistance exercise, and vigilant monitoring of vulnerable patients remain part of the prescription.

Subject of Research: Body composition changes and sarcopenia risk during incretin-based obesity therapy

Article Title: Losing Muscle or Restoring Physiology? Reframing the Incretin Therapy Sarcopenia Concern

Article References: Koufakis, T., Tentolouris, A., Karakasis, P., Popovic, D. S., & Patoulias, D. (2026). Losing Muscle or Restoring Physiology? Reframing the Incretin Therapy Sarcopenia Concern. Advances in Therapy. https://doi.org/10.1007/s12325-026-03804-z

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03804-z

Keywords: incretin therapy, semaglutide, tirzepatide, obesity, sarcopenia, lean body mass, body composition, skeletal muscle, resistance exercise, muscle quality, bariatric surgery, cardiometabolic health

The research, published in Physiological Reports, followed 50 sports-active men and women who suffered acute strain injuries to either the calf or hamstring muscles. Using a quantitative magnetic resonance imaging technique called DIXON, the team measured the fat fraction of the entire injured muscle volume in the first week after injury, then again at three months and twelve months post-injury. DIXON imaging separates water and fat signals within tissue, generating water-only and fat-only images that allow researchers to calculate precisely how much of a muscle’s volume is occupied by fat rather than contractile tissue.

The findings were striking in their clarity. Acutely after injury, there was no measurable difference in fat content between the injured and uninjured legs. But by three months, the injured muscles showed significantly higher fat fractions than their healthy counterparts, and this elevation remained unchanged at the twelve-month follow-up. The uninjured legs showed no such change across the entire year, confirming that the effect was specific to the damaged tissue. Notably, all participants had returned to full sports participation at a median of 48 days after injury, meaning the persistent fat accumulation occurred despite active loading and rehabilitation of the muscles.

The study also uncovered meaningful relationships between fat accumulation and other measures of injury severity. Muscle volume loss correlated negatively with the rise in fat content between the acute scan and the three-month follow-up, suggesting that the more contractile tissue a muscle loses, the more fat it accumulates in its place. The team additionally found a positive correlation between enlargement of the aponeurosis, the fibrous sheet into which muscle fascicles insert, and the increase in fat fraction at three months. This hints at a deeper story about how the muscle and its connective tissue framework fail to re-establish their normal mechanical coupling after injury.

Previous work had already hinted at lasting structural changes after strain injuries. Tissue biopsies from previously injured muscles have shown fat accumulation both inside and between muscle cells that could not be reversed by three months of rehabilitation training, and electron microscopy of chronic injury sites has revealed a loss of contractile elements. Ultrasound imaging has further suggested that muscle fascicles at the injury site fail to contract normally, instead being passively dragged along by the aponeurosis during movement. The new imaging data extend these observations to the whole-muscle level and establish a clear timeline for when fatty infiltration first appears.

The researchers propose that a fundamental defect at the muscle-aponeurosis interface may drive the process. When muscle fascicles cannot generate proper tension at their insertion points, the biomechanical cues within the tissue change, potentially altering the behavior of resident cells. Fibro/adipogenic progenitors, a heterogeneous population of cells capable of differentiating into either fat or fibrous tissue, have been implicated in fatty infiltration in animal models. Whether these cells are responsible for the fat accumulation seen in human strain injuries remains unknown, but the persistent, seemingly irreversible nature of the change points to a fundamental shift in the local cellular environment rather than a simple consequence of disuse.

The clinical implications are significant. Fatty infiltration is recognized as a major contributor to impaired muscle quality and is a strong predictor of poor recovery and high recurrence rates in rotator cuff tears. If similar processes operate in the hamstring and calf muscles, where re-injury rates are notoriously high, the persistent fat accumulation documented here could help explain why so many athletes suffer repeated strains at the same site. The current findings suggest that rehabilitation protocols may need to address not just strength and flexibility but the underlying structural integrity of the muscle-tendon unit.

One of the study’s key methodological strengths was its measurement of fat across the entire three-dimensional muscle volume rather than in a single representative slice, an approach that other work has shown is more reliable for capturing the true extent of infiltration. The team also took care to exclude the outer edge of the muscle near subcutaneous fat deposits to ensure that only intramuscular fat was quantified. The researchers acknowledge certain limitations, including the resolution limits of the DIXON technique at the low fat fractions observed and the inability to analyse fat distribution at the specific injury site, which could hypothetically show even greater local accumulation.

Looking ahead, the team emphasises that the cellular mechanisms underlying this rapid and persistent fatty infiltration remain poorly understood. Future work will need to determine whether affected muscle fibres retain their nerve supply, whether they can generate contractile force, and how the interplay between mechanical loading, connective tissue structure and progenitor cell behaviour drives the process. For now, the message for athletes and clinicians is sobering: a muscle strain leaves a measurable metabolic and structural fingerprint that persists long after the pain has gone and normal training has resumed, and current rehabilitation approaches may not be sufficient to prevent it.

Subject of Research: Persistent fatty infiltration in skeletal muscle following acute strain injuries in sports-active adults

Article Title: Early and persisting increase in fat content after human muscle strain injuries in adults

Article References: Bayer, M. L., Mertz, K. H., Eriksen, A. S., Kjaer, M., Magnusson, S. P., Linden, F. H., & Svensson, R. B. (2026). Early and persisting increase in fat content after human muscle strain injuries in adults. Physiological Reports, 14(17), Article e71086. https://doi.org/10.14814/phy2.71086

Image Credits: AI Generated

DOI: 10.14814/phy2.71086

Keywords: muscle strain injury, fatty infiltration, DIXON MRI, aponeurosis, hamstring injury, calf injury, sports injury, muscle volume, fat fraction, rehabilitation, reinjury, muscle quality