A High-Fat Diet Aggravates the Age-Related Decline in Skeletal Muscle Structure and Function

Hans Degens; Anandini Swaminathan; Jason Tallis


Exerc Sport Sci Rev. 2021;49(4):253-259. 

In This Article

Causes and Mechanisms of Skeletal Muscle Dysfunction During HFD and Obesity

Aging is associated with reduced levels of physical activity in all sorts of organisms, including humans, which contributes to the age-related decrements in skeletal muscle mass and function.[1] In fact, when adjusted for height, level of physical activity, pain, depression, and muscle mass, obesity-induced increases in hand-grip strength, peak isometric force of the elbow extensors, and peak isometric force of the knee extensors in older women were no longer apparent.[28] This suggests that a significant part of the problems in overweight is attributable to lower levels of physical activity.

Although reduced physical activity apparently contributes significantly to the muscle dysfunction in obesity, an HFD itself may also play an important role. As discussed previously, the IMCL content in type I fibers was negatively related to the specific power of human type I fibers,[24] and IMCL occurred earlier in old than in young-adult HFD fed mice.[19] The earlier accumulation of IMCL during an HFD in old than in younger muscles[19] is perhaps due to a substantially greater adiposity in normal old[10] than that seen in normal young-adult mice.[23] The larger adiposity may in turn result in the diversion of storage of the excessive fatty acids from an HFD in skeletal muscle fibers rather than in adipose tissue.

Another explanation for earlier accumulation of IMCL in old than in young-adult mice on an HFD may be due to a compensatory increase in oxidative capacity in the muscle fibers of young-adult,[25] but not old, animals[19] that would enhance the capacity for fatty acid oxidation. In support of this, it has been observed in mice that an HFD increases the expression of fatty acid binding protein and the rate-limiting enzyme of fatty acid oxidation, m-carnitine palmitoyl transferase (m-CPT-I).[26] Such an increased capacity for fatty acid oxidation may at least transiently stave off the accumulation of IMCL and the associated muscle dysfunction. Indeed, in a mouse model of lipotoxic cardiomyopathy, the uptake of fatty acids by cardiomyocytes exceeded the use of fatty acids and led to cardiac dysfunction.[29] In addition, CD36 (the membrane-bound fatty acid transporter) deficiency diminished IMCL accumulation and the increase in body mass during an HFD, but led to enhanced liver steatosis.[26] Therefore, the absence of a significant HFD-induced increase in oxidative capacity may well be a factor underlying the earlier rise in body mass, BMI, and IMCL accumulation in old than in young-adult animals.[19]

In addition to IMCL accumulation, in mice, an HFD has also been associated with oxidative stress that was mitigated by CD36 deficiency.[26] This suggests that perhaps some of the lipotoxicity is a consequence of oxidative stress resulting from the accumulation of IMCL. If so, IMCL accumulation may mediate a reduction in the HFD-induced reduction in specific tension and specific power via both a reduced myofibrillar volume and increased oxidation of myofibrillar proteins.

The HFD-induced increase in muscle oxidative capacity[19,25] was not accompanied by a commensurate capillary proliferation, resulting in a morphological mismatch between the oxygen supply — reflected by the capillarization — and demand — reflected by the oxidative capacity — in muscle fibers from mice on an HFD.[19] Although the increased resting red blood cell flux after 8 wk of HFD in mice[25] perhaps at least initially compensated for the reduced morphological mismatch between supply and demand at rest, the morphological mismatch may well limit the oxygen supply during exercise. In obese Zucker rats, capillary rarefaction has even been observed.[30]

As capillarization is important for muscle function,[31] and such a reduction in muscle capillarization also occurs in humans, this undoubtedly contributes to the impaired exercise tolerance in obese individuals.

The Figure illustrates our hypothesis. We speculate that IMCL accumulation during an HFD may be accelerated in older people as a consequence of diversion of lipid storage from already loaded adipose tissue to skeletal muscle. The accumulation of IMCL as a consequence of an HFD may cause skeletal muscle dysfunction via lipotoxicity that is to some extent staved off by increasing the capacity for fatty acid oxidation in young-adult but not old muscles. The impact on exercise capacity is aggravated by capillary rarefaction that results in a mismatch between oxygen supply and demand.


A high-fat diet (HFD) leads to an earlier accumulation of intramyocellular lipids (ICML) in muscles from old than young-adult mice. On the left hand side is the duration of HFD in weeks (w). The clouds illustrate the progressive increase in adiposity (shown as increasing size of the clouds) up to a point (indicated as full) beyond which further lipid accumulation in adipose tissue is reduced (indicated by the circle with a diagonal line). Here, we suggest that the larger adiposity in old than young mice limits the ability to store additional lipids in adipose tissue. In addition, whereas in young mice an HFD induced an increase in oxidative capacity (reflected by the darker-stained ovals and the larger number of mitochondria icons), enhancing the ability to perform fatty acid oxidation, this was not the case in muscles from old animals. Thus, the higher need to store excessive lipids in muscle, as the adipose tissue is progressively filling up, and the lower ability to use fatty acids, as reflected by the absence of an HFD-induced rise in oxidative capacity in old muscles, results in an earlier accumulation of IMCL and muscle dysfunction in old than in young animals.