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Cited by 521Muscle Physiology and DisordersMuscle metabolism and nutritionCardiovascular and exercise physiology

Sex-Based Differences in Skeletal Muscle Kinetics and Fiber-Type Composition

Open access
Haizlip, K. M., Harrison, B. C., Leinwand, L. A.·2015·Physiology
DOI 10.1152/physiol.00024.2014PMC PMC4285578
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Abstract

Previous studies have identified over 3,000 genes that are differentially expressed in male and female skeletal muscle. Here, we review the sex-based differences in skeletal muscle fiber composition, myosin heavy chain expression, contractile function, and the regulation of these physiological differences by thyroid hormone, estrogen, and testosterone. The findings presented lay the basis for the continued work needed to fully understand the skeletal muscle differences between males and females.

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Written from the paper’s full text.

TL;DR

This review summarizes sex-based differences in skeletal muscle fiber-type composition, myosin heavy chain expression, contractility, fatigue, and hormonal regulation by thyroid hormone, estrogen, and testosterone. It concludes that females generally have a higher prevalence of slower, more oxidative type-I/IIA fibers and greater endurance/recovery, while males tend to have faster contractile kinetics and greater fatigability.

Key findings

  • More than 3,000 genes are differentially expressed between male and female skeletal muscle. In human vastus lateralis, female muscle has 35% more MyHC-I/β, 30% less MyHC-IIa, and 15% less MyHC-IIx mRNA than male muscle; type-I fibers account for 44% of biopsy area in women vs. 36% in men, while type-IIA fibers account for 34% in women vs. 41% in men.
  • Contractile and fatigue differences are reported: mouse masseter maximal rate of force generation is higher in males (516 vs. 382 g/s), and relaxation is faster in males (41 vs. 48 ms). Endurance is lower in men than women in some studies (11 vs. 18 min; elbow flexor 829 s in males vs. 1,806 s in females), and in adductor pollicis force falls to ∼93% of maximum in women vs. 80% in men after <1 min of exercise.
  • Hormonal regulation shows sex-specific effects. T3 treatment in rat soleus produces different fiber-type profiles in males (73% type-I/IIA, 26% type-I/IIAX) vs. females (37% type-I, 49% type-I/IIA, 6% type-I/IIAX). Ovariectomy reduces maximal isometric tetanic force from sham 180 mN to 168 mN, attenuated to 187 mN with estrogen; strong-binding myosin is 0.263 in OVX vs. 0.300 sham and 0.311 with estrogen.
  • Testosterone-related morphology: in human vastus lateralis, type-I fibers are 19% larger, type-IIA fibers 59% larger, and type-IIX fibers 66% larger in men than women.

Methods

  • Narrative review of sex-based differences in skeletal muscle fiber composition, myosin heavy chain expression, contractile function, and regulation by thyroid hormone, estrogen, and testosterone.
  • Evidence is synthesized from cited human and animal studies, including human vastus lateralis biopsies and rodent, rabbit, guinea pig, and canine muscle models; no new primary data are presented.
  • Main analysis is literature synthesis, with summary tables for fiber-type expression, baseline contractility, thyroid hormone effects, and ERβ-null mouse data.

Limitations

  • The paper states that studies investigating sex-based differences in muscle fiber type are somewhat limited, that experimental models often study only males because sex is thought to confound results, and that further investigations are needed; it also notes that one or two genes cannot explain all sex differences.
  • Evident from the text: this is a narrative review without a systematic search or meta-analysis, and findings are heterogeneous across species, muscles, ages, and methods; some cited results are contradictory, such as T3 effects on shortening velocity, and some mechanisms remain uninvestigated, including calcium storage capacity after ovariectomy.

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Integrity signals

Registry

Crossref · 10.1152/physiol.00024.2014

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation
    § Abstract

    All fibers measured in men have significantly larger cross-sectional areas (CSA) compared with women as normalized to biopsy section area.

    “Additionally, all of the fibers measured in men have significantly larger cross-sectional areas (CSA) compared with women as normalized to biopsy section area (89).”
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  • Premisecitation
    § Abstract

    Studies on chemically skinned human fibers reveal that MyHC isoform composition is the key determinant of muscle fiber contractile velocity and rate of force development.

    “Studies on chemically skinned human fibers reveal that MyHC isoform composition is the key determinant of muscle fiber contractile velocity and rate of force development (11, 72).”
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  • Interpretationcitation
    § Abstract

    There is evidence of sexual dimorphisms with respect to muscle fiber-type composition.

    “Although studies investigating sex-based differences in muscle fiber type are somewhat limited, there is also evidence of sexual dimorphisms with respect to muscle fiber-type composition (Table 2).”
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  • Interpretationreasoning
    § Abstract

    The difference in CSA between men and women seems likely to be due to the overall greater mass in males compared with females since the increase in CSA is nearly proportional to the differences in mass.

    “The difference in CSA seems likely to be due to the overall greater mass in males compared with females since the increase in CSA is nearly proportional to the differences in mass.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § Abstract

    More than 3,000 genes have been identified as differentially expressed between male and female skeletal muscle.

    “Previous studies have identified over 3,000 genes that are differentially expressed in male and female skeletal muscle.”
    • Also stated in: § Abstract · plain
      “More than 3,000 genes have been identified as being differentially expressed between male and female skeletal muscle (96).”
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    Findingnone given
    § Abstract

    In the mouse hindlimb, MyHC-IIa expression is higher in males vs. females in the soleus (58% in males vs. 36% in females) and tibialis anterior (39% in males vs. 25% in females), whereas in the plantaris, IIa expression is higher in females (37%) than in males (16%).

    “For example, MyHC-IIa expression is higher in males vs. females in the soleus (58% in males vs. 36% in females) and tibialis anterior (TA) (39% in males vs. 25% in females), whereas in the plantaris, IIa expression is higher in females (37%) than in males (16%).”
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    Premisecitation
    § Abstract

    The mouse masseter is composed of high numbers of IIX fibers in both sexes; however, there are threefold fewer IIB fibers and more IIA fibers in females compared with males.

    “The mouse masseter is composed of high numbers of IIX fibers in both sexes; however, there are threefold fewer IIB fibers and more IIA fibers in females compared with males (27).”
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    Premisecitation
    § Abstract

    Analysis of mRNA from male and female vastus lateralis biopsies by microarray shows (when normalized to α-actinin) that female muscle has 35% more MyHC-I/β, 30% less MyHC-IIa, and 15% less MyHC-IIx mRNA than corresponding male muscle.

    “Analysis of mRNA from both male and female vastus lateralis biopsies by microarray shows (when normalized to α-actinin) that the female muscle has 35% more MyHC-I/β, 30% less MyHC-IIa, and 15% less MyHC-IIx mRNA than the corresponding male muscle (96).”
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    Premisecitation
    § Abstract

    There are 11 myosin heavy chain (MyHC) genes that encode different myosin isoforms in mammals.

    “There are 11 myosin heavy chain (MyHC) genes that encode different myosin isoforms in mammals (77).”
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    Premisecitation
    § Abstract

    Type-I fibers account for 36% of the total biopsy area in men and 44% in women, whereas type-IIA fibers account for 41% in men and only 34% in women.

    “Type-I fibers account for 36% of the total biopsy area in men and 44% in women, whereas type-IIA fibers account for 41% in men and only 34% in women (89).”
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    Premisecitation
    § Abstract

    MyHC isoform expression directly affects muscle fiber-type contractile velocity via myosin ATPase activity, with relative velocities I < IIA < IIX < IIB.

    “Functionally, MyHC isoform expression directly affects muscle fiber-type contractile velocity via myosin ATPase activity (74), with relative velocities of I < IIA < IIX < IIB (73, 74).”
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    Premisecitation
    § Abstract

    Human skeletal muscle does not express MyHC-IIb protein, at least in part due to reduced activity of the human MyHC-IIb promoter region.

    “In contrast, human skeletal muscle does not express MyHC-IIb protein, a phenomenon that appears to be, at least in part, due to a reduction in the activity of the human MyHC-IIb promoter region (37).”
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    Premisecitation
    § Abstract

    Average MyHC isoform percentages in the male vastus lateralis are IIx (20%), IIa (46%), and I (34%), whereas female samples are IIx (23%), IIa (36%), and I (41%).

    “Overall, in this analysis, the average MyHC isoform percentages in the male vastus lateralis are IIx (20%), IIa (46%), and I (34%), whereas the females samples are IIx (23%), IIa (36%), and I (41%) (89).”
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    Interpretationnone given
    § Abstract

    Skeletal muscle fiber-type composition is dependent on species, anatomical location/function, and sex.

    “Overall, evidence to date suggests that skeletal muscle fiber-type composition is dependent on species, anatomical location/function, and sex.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Abstract

    Male rabbit masseter is comprised of nearly 80% type-IIA fibers, whereas the female masseter contains only ∼50%.

    “Male rabbit masseter is comprised of nearly 80% type-IIA fibers, whereas the female masseter contains only ∼50% (28).”
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    Premisecitation
    § Abstract

    Treatment of euthyroid animals with T3 induces hyperthyroidism, producing a reversible slow-to-fast MyHC isoform transition from I → IIa → IIx → IIb.

    “Treatment of euthyroid animals with T3 induces hyperthyroidism, producing a reversible slow-to-fast MyHC isoform transition from I → IIa → IIx → IIb (for review, see Ref. 78).”
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    Interpretationreasoning
    § Abstract

    These studies suggest a potential role for T3 in skeletal muscle contractility and in sex-based differences that may exist in the response to changing T3 levels but point to the need for further investigations.

    “These studies suggest a potential role for T3 in skeletal muscle contractility and in sex-based differences that may exist in the response to changing T3 levels but point to the need for further investigations.”
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    Premisecitation
    § Abstract

    Hormonal regulation of skeletal muscle development and contractility are well documented.

    “In fact, hormonal regulation of skeletal muscle development and contractility are well documented (29, 70).”
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    § Abstract

    Endurance is longer in women (15 min) compared with men (8 min), and after reaching exhaustion, recovery occurs faster in women than in men.

    “Endurance is longer in women (15 min) compared with men (8 min), and after reaching exhaustion, recovery occurs faster in women than in men (31).”
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    Premisecitation
    § Abstract

    T3 treatment in euthyroid animals leads to a conversion from IIA to IIB fibers in the EDL of young and old female rats vs. no transition in males.

    “T3 treatment in euthyroid animals leads to a conversion from IIA to IIB fibers in the EDL of young and old female rats vs. no transition in males (52).”
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    Premisecitation
    § Abstract

    Thyroid hormone (T3) can regulate MyHC gene expression.

    “Thyroid hormone (T3) can regulate MyHC gene expression (42).”
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    Interpretationreasoning
    § Abstract

    These studies suggest that force generation and relaxation are faster during fatigue in men compared with women, whereas endurance is higher and recovery is quicker in women than in men.

    “These studies suggest that force generation and relaxation are faster during fatigue in men compared with women, whereas endurance is higher and recovery is quicker in women than in men.”
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    Premisecitation
    § Abstract

    During menopause, the decline in estrogen levels is paralleled with a slight increase in injury risk and a decline in lean body mass.

    “During menopause, the decline in estrogen levels is paralleled with a slight increase in injury risk and a decline in lean body mass (9).”
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    Premisecitation
    § Abstract

    After treatment with T3, male rat soleus muscle expresses 73% type-I/IIA and 26% type-I/IIAX of the total fibers, whereas females express 37% type-I, 49% type-I/IIA, and only 6% type-I/IIAX fibers.

    “Specifically, after treatment with T3, male rat soleus muscle expresses 73% type-I/IIA and 26% type-I/IIAX of the total fibers, whereas females express 37% type-I, 49% type-I/IIA, and only 6% type-I/IIAX fibers (101).”
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    Premisecitation
    § Abstract

    Hypothyroid females appear to have a higher proportion of type-II fibers compared with hypothyroid males; however, type-II fiber atrophy occurs in hypothyroid female patients but not in males.

    “Hypothyroid females appear to have a higher proportion of type-II fibers compared with hypothyroid males; however, type-II fiber atrophy occurs in hypothyroid female patients but not in males (63).”
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    Premisecitation
    § Abstract

    Four weeks of T3 treatment induces an increase in type-IIA fibers and a downregulation of type-I fibers in male and female rat soleus muscle.

    “Four weeks of T3 treatment induces an increase in type-IIA fibers and a downregulation of type-I fibers in male and female rat soleus muscle (57, 101).”
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    Premisecitation
    § Abstract

    The increase in IIX content from the type-I/IIAX fibers is greater in young T3-treated males (21%) than females (10%), and the upregulation of IIA is greater in young females (43%) than in young males (27%).

    “Overall, the increase in IIX content from the type-I/IIAX fibers is greater in young T3-treated males (21%) than females (10%), and the upregulation of IIA is greater in young females (43%) than in young males (27%) (101).”
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    Premisecitation
    § Abstract

    After intermittent bouts of isometric contraction (5 s on and 5 s off) in the adductor pollicis muscle, women fatigue more slowly and to a smaller degree than men.

    “After intermittent bouts of isometric contraction (5 s on and 5 s off) in the adductor pollicis muscle, women fatigue more slowly and to a smaller degree than men (31).”
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    Premisecitation
    § Abstract

    In another study of euthyroid animals, treatment with T3 induces expression of IIX in the soleus of aged male rats (4-15%), whereas there is no detectable IIX in females at any age.

    “In another study of euthyroid animals, treatment with T3 induces expression of IIX in the soleus of aged male rats (4–15%), whereas there is no detectable IIX in females at any age (52).”
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    Interpretationreasoning
    § Abstract

    These studies highlight the differences in fiber-type conversion as it relates to sex and pinpoints the differences in IIx expression in males and females.

    “These studies highlight the differences in fiber-type conversion as it relates to sex and pinpoints the differences in IIx expression in males and females.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Abstract

    Animal models of low estrogen levels, which occur after ovariectomy (OVX), reveal an increase in overall body mass and in the mass of individual muscles.

    “Animal models of low estrogen levels, which occur after ovariectomy (OVX), reveal an increase in overall body mass and in the mass of individual muscles (68).”
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    Premisecitation
    § Abstract

    Although forces exerted by both young men and women are not significantly different, endurance is lower for men than for women (11 vs. 18 min).

    “Although forces exerted by both young men and women are not significantly different, endurance is lower for men than for women (11 vs. 18 min) (39).”
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    Premisecitation
    § Abstract

    OVX leads to an increase in overall body weight and muscle weight, and a 70% increase in ERα mRNA with no change in ERβ mRNA.

    “OVX leads to an increase in overall body weight and muscle weight (68), and a 70% increase in ERα mRNA with no change in ERβ mRNA (7).”
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    Interpretationcitation
    § Abstract

    Estrogen has been shown to influence fiber size, overall muscle weight, muscle regeneration, and contractility, and to induce minimal changes in fiber-type distribution.

    “Estrogen has been shown to influence fiber size, overall muscle weight, muscle regeneration, and contractility, and to induce minimal changes in fiber-type distribution.”
    Quote in the paperSubstantial claim

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    Interpretationown data
    § Abstract

    Overall, ERβ deletion increases the contractile time and decreases the speed of contractile kinetics in both males and females.

    “Overall, ERβ deletion increases the contractile time and decreases the speed of contractile kinetics in both males and females.”
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    Interpretationcitation
    § Abstract

    This decline in regenerative capacity is thought to be directly related to findings that estrogen is associated with maintenance of muscle strength in pre- and postmenopausal women and suggests a role for ERs in skeletal muscle maintenance.

    “This decline in regenerative capacity is thought to be directly related to findings that estrogen is associated with maintenance of muscle strength in pre- and postmenopausal women (69) and suggests a role for ERs in skeletal muscle maintenance (64, 84, 85, 88).”
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    Premisecitation
    § Abstract

    The fraction of strong binding myosin in OVX muscle is 0.263 or ∼15% lower than baseline. Following estrogen treatment, the fraction of strongly bound myosin increases to 0.311, which is indistinguishable from sham levels (0.300).

    “The fraction of strong binding myosin in OVX muscle is 0.263 or ∼15% lower than baseline (67, 68). Following estrogen treatment, the fraction of strongly bound myosin increases to 0.311, which is indistinguishable from sham levels (0.300) (67).”
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    Premisecitation
    § Abstract

    Relaxation time during a basic contraction in the soleus is significantly shorter in wild-type males (104 ms) than in females (158 ms) and in null males (104 ms) compared with null females (191 ms).

    “Relaxation time during a basic contraction in the soleus is significantly shorter in wild-type males (104 ms) than in females (158 ms) and in null males (104 ms) compared with null females (191 ms).”
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    Interpretationreasoning
    § Abstract

    Because of the OVX-induced decrease in tetanic force, which requires rapid replenishment and utilization of calcium stores, and the increase in fiber diameter, which could compensate for a decline in calcium sensitivity, calcium handling and sensitivity may be playing a role in the regulation of contractile differences in samples with and without estrogen.

    “Because of the OVX-induced decrease in tetanic force, which requires rapid replenishment and utilization of calcium stores, and the increase in fiber diameter, which could compensate for a decline in calcium sensitivity, calcium handling and sensitivity may be playing a role in the regulation of contractile differences in samples with and without estrogen.”
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    Premisecitation
    § Abstract

    Ronkainen et al. found that HRT is associated with better mobility, greater muscle power, and favorable body and muscle composition in women ages 54-62.

    “Ronkainen et al. (76) found that HRT is associated with better mobility, greater muscle power, and favorable body and muscle composition in women ages 54–62 (76).”
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    Premisecitation
    § Abstract

    Analysis of contractile function in OVX mice reveals a significant decrease in maximal isometric tetanic force from sham levels (180 mN) to 168 mN. This decline is attenuated to 187 mN with estrogen supplementation.

    “Analysis of contractile function in OVX mice reveals a significant decrease in maximal isometric tetanic force from sham levels (180 mN) to 168 mN (67, 68). This decline is attenuated to 187 mN with estrogen supplementation (67).”
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    Interpretationcitation
    § Abstract

    In the studies referenced in the previous sections, there is no change in MyHC isoform expression or overall muscle fiber-type composition, but there are estrogen-related changes in fiber-type diameter, muscle size, contractility, and the actin-myosin interaction.

    “In the studies referenced in the previous sections, there is no change in MyHC isoform expression or overall muscle fiber-type composition, but there are estrogen-related changes in fiber-type diameter, muscle size, contractility, and the actin-myosin interaction.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Abstract

    In rat soleus and EDL muscles, OVX leads to a slight increase in the mean fiber diameter of type-I, -IIA, and -IIB fibers. Estrogen supplementation decreases fiber diameter in all fiber types in both the soleus and EDL significantly from OVX levels to below baseline levels.

    “In rat soleus and EDL muscles, OVX leads to a slight increase in the mean fiber diameter of type-I, -IIA, and -IIB fibers. Estrogen supplementation decreases fiber diameter in all fiber types in both the soleus and EDL significantly from OVX levels to below baseline levels (90).”
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    Premisecitation
    § Abstract

    In male and female vastus lateralis muscle, expression of ERα mRNA is 180-fold higher than ERβ, with no significant difference in expression levels between males and females.

    “In male and female vastus lateralis muscle, expression of ERα mRNA is 180-fold higher than ERβ, with no significant difference in expression levels between males and females (98).”
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    Premisecitation
    § Abstract

    OVX induces a reduction in time to peak tension and increases time to 50% relaxation in rats, whereas estrogen replacement reverses the OVX-induced reduction in peak tension.

    “OVX induces a reduction in time to peak tension and increases time to 50% relaxation in rats, whereas estrogen replacement reverses the OVX-induced reduction in peak tension (62).”
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    Premisecitation
    § Abstract

    Skeletal muscle expresses two forms of ERs (α and β), and the effects of estrogen are mediated, in part, through these receptors.

    “Skeletal muscle expresses two forms of ERs (α and β), and the effects of estrogen are mediated, in part, through these receptors (14, 21, 56, 98).”
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    Premisecitation
    § Abstract

    Studies on muscle repair following exercise-induced injury highlight a sex-based difference in which higher levels of muscle creatine kinase (indicative of injury) are observed in male than in female rats following injury. Following OVX, levels of muscle creatine kinase in females are similar to levels in injured males.

    “Studies on muscle repair following exercise-induced injury highlight a sex-based difference in which higher levels of muscle creatine kinase (indicative of injury) are observed in male than in female rats following injury. Following OVX, levels of muscle creatine kinase in females are similar to levels in injured males (3, 4, 8).”
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    Premisecitation
    § Abstract

    There is no sexually dimorphic expression in either ERα or ERβ in skeletal muscle.

    “As stated previously, there is no sexually dimorphic expression in either ERα or ERβ in skeletal muscle (98).”
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    Premisecitation
    § Abstract

    Following a fatiguing protocol on soleus and EDL muscle, force decreases less in ERβ−/− males than in wild-type males, whereas the reverse is true for females, suggesting a role for ERβ knockout in enhancing endurance in males and reducing endurance in females.

    “Following a fatiguing protocol on soleus and EDL muscle, force decreases less in ERβ−/− males than in wild-type males, whereas the reverse is true for females, suggesting a role for ERβ knockout in enhancing endurance in males and reducing endurance in females (33).”
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    Premisecitation
    § Abstract

    Recent studies suggest a beneficial role for hormone replacement therapy (HRT), supplementation with estrogen and progesterone, and the induction of pathways by which estrogen can aide in skeletal muscle maintenance and repair.

    “Recent studies suggest a beneficial role for hormone replacement therapy (HRT), supplementation with estrogen and progesterone, and the induction of pathways by which estrogen can aide in skeletal muscle maintenance and repair (71).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    ERα-null mice have a decreased muscle regenerative capacity following injury, as evidenced by small myofibers and centrally located nuclei.

    “ERα-null mice have a decreased muscle regenerative capacity following injury, as evidenced by small myofibers and centrally located nuclei (50).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Taken together, these findings on estrogen and the ER-mediated regulation of the contractile response and fiber-type distribution suggest a role for estrogen and its receptors in contractile maintenance and function, with a differential effect of estrogen in males vs. females.

    “Taken together, these findings on estrogen and the ER-mediated regulation of the contractile response and fiber-type distribution suggest a role for estrogen and its receptors in contractile maintenance and function, with a differential effect of estrogen in males vs. females.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    In mice, although overall muscle weight increases, the fiber CSA of the soleus and TA do not significantly change.

    “In mice, castration produces a decrease in body weight, which is attenuated with testosterone supplementation, and although overall muscle weight increases, the fiber CSA of the soleus and TA do not significantly change (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    With advancing age, testosterone levels drop, and testosterone deficiency is associated with early death, primarily from cardiovascular disease, a decrease in muscle mass and/or strength, and sexual dysfunction.

    “With advancing age, testosterone levels drop, and testosterone deficiency is associated with early death, primarily from cardiovascular disease, a decrease in muscle mass and/or strength, and sexual dysfunction (46).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    ARs are widely expressed in myoblasts, myofibers, and motoneurons in both males and females, and testosterone injected into the masseter of female guinea pigs leads to an increase in fiber size.

    “ARs are widely expressed in myoblasts, myofibers, and motoneurons in both males and females (17, 100), and testosterone injected into the masseter of female guinea pigs leads to an increase in fiber size (35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] source

      Not checked in the free run.

    • cites [100] source

      Not checked in the free run.

    • cites [35] Gutmann E, 1970, Histochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Testosterone is a highly studied androgen that is associated with an increase in muscle mass.

    “Testosterone is a highly studied androgen that is associated with an increase in muscle mass (66, 83).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] source

      Not checked in the free run.

    • cites [83] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Testosterone has been shown to induce its effects through binding to intracellular androgen receptors (ARs), which then regulate gene transcription.

    “Testosterone has been shown to induce its effects through binding to intracellular androgen receptors (ARs) (34), which then regulate gene transcription (18, 81).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] source

      Not checked in the free run.

    • cites [18] source

      Not checked in the free run.

    • cites [81] Simental JA, 1991, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Analysis of fiber-type distribution in hypogonadal male vs. female mice reveals no significant changes in type-I, -IIA, -IIX, or -IIB fibers in gastrocnemius muscle or in type-I or -IIA fibers in the soleus.

    “Analysis of fiber-type distribution in hypogonadal males vs. females reveals no significant changes in type-I, -IIA, -IIX, or -IIB fibers in gastrocnemius muscle or in type-I or -IIA fibers in the soleus (79).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    In AR-null males, force production decreases in fast-twitch fibers, whereas fatigue resistance increases in slow-twitch fibers to levels similar to wild-type females.

    “Additionally, in AR-null males, force production decreases in fast-twitch fibers, whereas fatigue resistance increases in slow-twitch fibers to levels similar to wild-type females (59).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    In mice, castration produces a decrease in body weight that is attenuated with testosterone supplementation.

    “In mice, castration produces a decrease in body weight, which is attenuated with testosterone supplementation, and although overall muscle weight increases, the fiber CSA of the soleus and TA do not significantly change (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    In hypogonadal mice, gastrocnemius fiber-type distribution is relatively unchanged from wild-type mice, with relative contribution I < IIX < IIA < IIB in both males and females.

    “Additionally fiber-type distribution of the gastrocnemius is relatively unchanged from wild-type mice, with I < IIX < IIA < IIB being the relative contribution of each fiber-type in males and females (79).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    In vastus lateralis biopsies, fiber-type cross-sectional area is larger in men than in women; type-I fibers are 19% larger, type-IIA fibers are 59% larger, and type-IIX fibers are 66% larger in men than in women (normalized to total biopsy section analyzed).

    “As mentioned earlier, studies of vastus lateralis biopsies show fiber-type CSA to be larger in men than in women. Specifically, type-I fibers are 19% larger, type-IIA fibers are 59% larger, and type-IIX fibers are 66% larger in men than in women (normalized to total biopsy section analyzed) (89).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning
    § Abstract

    These anabolic effects of testosterone are well characterized and provide the catalysts for further investigation of the response of muscle fiber-type composition to testosterone deficiency and supplementation in males and females.

    “These anabolic effects of testosterone are well characterized and provide the catalysts for further investigation of the response of muscle fiber-type composition to testosterone deficiency and supplementation in males and females.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § Abstract

    During fatigue, where females typically have greater endurance, ERβ elimination decreases the endurance in the female and enhances endurance in the male.

    “During fatigue, where females typically have greater endurance, ERβ elimination decreases the endurance in the female and enhances endurance in the male.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Testosterone supplementation leads to an increase in muscle mass and a decrease in fat content in hypogonadal men.

    “Testosterone supplementation leads to an increase in muscle mass and a decrease in fat content in hypogonadal men (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Brodsky IG, 1996, J Clin Endocrinol Metab

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    GRB10 knockout in male and female mice produces an increase in muscle weight and a decrease in body fat percentage, thus enhancing muscularity.

    “GRB10 knockout in male and female mice produces an increase in muscle weight and a decrease in body fat percentage and thus enhances muscularity (86).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Testosterone deficiency leads to a decline in body mass, a decrease in fast-twitch fiber diameter, a conversion to slow-twitch fibers, and enhanced fatigue resistance in males but not females.

    “Testosterone deficiency leads to a decline in body mass, a decrease in fast-twitch fiber diameter, a conversion to slow-twitch fibers, and enhanced fatigue resistance in males but not females.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Conclusions

    In the study by Welle et al., two genes upregulated in women compared with men are GRB10 and ACVR2A, which code for proteins in signaling pathways of growth factors known to regulate muscle mass.

    “In this study, the authors focus on two particular genes that are upregulated in women compared with men and that are known to code for proteins that are in signaling pathways of growth factors known to regulate muscle mass: growth factor receptor-bound protein 10 (GRB10) and activin receptor type-2A (ACVR2A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Conclusions

    Estrogen and testosterone are implicated in skeletal muscle growth, fiber size, and minimally in contractile function.

    “Although thyroid hormone induces a conversion from slow to fast fibers and increases contractile velocity, sex-specific hormones estrogen and testosterone are implicated in skeletal muscle growth, fiber size, and minimally in contractile function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given
    § Conclusions

    Sex-based differences in skeletal muscle fiber-type composition and function are apparent in numerous species and are present in specific anatomical locations.

    “Sex-based differences in skeletal muscle fiber-type composition and function are apparent in numerous species and are present in specific anatomical locations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given
    § Conclusions

    There is a prevalence of slower type-I and -IIA fibers in females compared with males that parallels the lower contractile velocity in females compared with males.

    “There is a prevalence of slower type-I and -IIA fibers in females compared with males that parallels the lower contractile velocity in females compared with males.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In adult mammalian muscle, the four main MyHC isoforms (MyHC-I, -IIa, -IIx, and -IIb) increase in contractile speed in that order.

  • May combine two claims.

    Interpretationcitation
    § Abstract

    Testosterone can induce its effects via either estrogen receptors or androgen receptors.

    “Because aromatase converts testosterone to estrogen (60), testosterone can induce its effects via either ERs or ARs, thus this contractile effect is thought to be mediated by the activation of ERs.”
    Quote in the paperSubstantial claim
67 of 67

  • The paper relies on this without support.

    Sex is often thought to confound results in experimental models, so usually only males are studied.

    “This is often the case in experimental models where sex is thought to confound results and therefore usually only males are studied.”

  • The paper relies on this without support.

    A strong actin-myosin bond produces a greater force.

    “Since a strong actin-myosin bond will produce a greater force, this has been measured in muscles with and without estrogen manipulation.”

  • The paper relies on this without support.

    In adult mammalian muscle, the four main MyHC isoforms (MyHC-I, -IIa, -IIx, and -IIb) increase in contractile speed in that order.

    “There are four main MyHC isoforms present in adult mammalian muscle (MyHC-I, -IIa, -IIx, and -IIb), which increase in contractile speed in the presented order.”

  • The paper relies on this without support.

    Thyroid hormone induces a conversion from slow to fast fibers and increases contractile velocity.

    “Although thyroid hormone induces a conversion from slow to fast fibers and increases contractile velocity, sex-specific hormones estrogen and testosterone are implicated in skeletal muscle growth, fiber size, and minimally in contractile function.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Many physiological factors differ significantly between biological males and females as a result of genetic differences and androgen-directed development of secondary sex characteristics.

    “Many of these physiological factors differ significantly between biological males and females as a result of genetic differences and androgen-directed development of secondary sex characteristics [3, 4].”

    From Transgender Women in the Female Category of Sport: Perspectives on Testosterone Suppression and Performance Advantage (2021) · cites this paper as [3]

    The Abstract reports sex differences in skeletal-muscle physiology and gene expression, and the Conclusions implicate testosterone in muscle growth and fiber size (page numbers unavailable). The paper does not establish that broad physiological differences result from genetic differences or androgen-directed development of secondary sex characteristics; its discussion is focused on skeletal muscle. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Males have superior cardiovascular and respiratory function compared with females, with larger blood and heart volumes, higher hemoglobin concentration, greater cross-sectional area of the trachea and lower oxygen cost of respiration.

    “superior cardiovascular and respiratory function, with larger blood and heart volumes, higher hemoglobin concentration, greater cross-sectional area of the trachea and lower oxygen cost of respiration [3, 4, 39, 40].”

    From Transgender Women in the Female Category of Sport: Perspectives on Testosterone Suppression and Performance Advantage (2021) · cites this paper as [3]

    The Abstract mentions sex-based differences in cardiovascular health and disease, but does not describe males as having superior cardiovascular or respiratory function. Searches for blood and heart volume, hemoglobin, tracheal area, and the oxygen cost of respiration found no passage in our copy addressing those comparisons. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Hypothyroidism table reverses the stated type-II fiber change

    Minor

    The prose says hypothyroidism lowers the type-II fiber percentage in both sexes relative to healthy patients, while Table 4 marks type-II fibers as increasing in both sexes.

  • Wild-type male soleus relaxation time differs from Table 5

    Minor

    The prose gives wild-type males a soleus relaxation time of 104 ms, whereas Table 5 reports 100.4 ms. The prose's 104 ms matches the table's null-male value instead.

  • Claim of no fiber-type composition change conflicts with plantaris results

    Minor

    The later summary says the referenced studies found no change in overall fiber-type composition, but the preceding plantaris results report type-IIX composition changing after ovariectomy and estrogen supplementation.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Brodsky IG, 1996, J Clin Endocrinol Metab, 81, 3469
  2. MacIntosh BR, 2003, News Physiol Sci, 18, 222
  3. Maggiolini M, 1999, Cancer Res, 59, 4864

Cited by

Sorted by citations

Related

Authors
Haizlip, K. M., Harrison, B. C., & Leinwand, L. A.
Affiliations
University of Colorado Boulder (US)
Corresponding author
Leinwand, L. A.
ORCID
Venue
Physiology
Publisher
American Physiological Society
Published
2015-01
Volume
30
Issue
1
Pages
30-39
ISSN
  • 0886-1714 (ISSN-L)
  • 1548-9213
  • 1548-9221
DOI
10.1152/physiol.00024.2014
PMC
PMC4285578
OpenAlex
W2097561994
Semantic Scholar
b290b0c3482c23b4612ebb91c3677997d764978e
Cited by
521
References
157
Citations by year
2026: 52 · 2025: 79 · 2024: 89 · 2023: 65 · 2022: 69 · 2021: 49 · 2020: 37 · 2019: 41 · 2018: 20 · 2017: 8 · 2016: 7 · 2015: 4
FWCI
1.25
Type
journal article
Language
en
Open access
Locations
  • Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (T32HL007822)
  • National Institute of General Medical Sciences (GM-029090-30A1S1, GM-29090-31, R01GM029090)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR055676)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Keywords
sex differences, skeletal muscle, muscle fiber composition, myosin heavy chain, muscle contractility, thyroid hormones, estrogen, testosterone, gene expression
MeSH terms
Animals, Female, Humans, Kinetics, Male, Muscle Contraction, Sex Characteristics, Thyroid Hormones, Muscle Fibers, Skeletal, Myosin Heavy Chains

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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